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Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury Elliot J. Glotfelty, Thomas Delgado, Luis B. Tovar-y-Romo, Yu Luo, Barry Hoffer, Lars Olson, Tobias Karlsson, Mark Mattson, Brandon Harvey, David Tweedie, Yazhou Li, and NIGEL GREIG ACS Pharmacol. Transl. Sci., Just Accepted Manuscript • DOI: 10.1021/acsptsci.9b00003 • Publication Date (Web): 11 Feb 2019 Downloaded from http://pubs.acs.org on February 11, 2019

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ACS Pharmacology & Translational Science

Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury Elliot J. Glotfelty1,5, Thomas Delgado1, Luis B Tovar-y-Romo2, Yu Luo3, Barry Hoffer4, Lars Olson5, Tobias Karlsson5, Mark P. Mattson6, Brandon Harvey7, David Tweedie1, Yazhou Li1, Nigel H. Greig1

1

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National

Institutes of Health, Baltimore, MD 21224, USA 2Division

of Neuroscience, Institute of Cellular Physiology, Universidad Nacional Autónoma de México,

Mexico City, Mexico 3Department

4Department

of Molecular Genetics, University of Cincinnati, Cincinnati, OH 45221, USA of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH

44106, USA 5Department

6

of Neuroscience, Karolinska Institutet, Stockholm, Sweden

Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National

Institutes of Health, Baltimore, MD 21224, USA 7Molecular

Mechanisms of Cellular Stress and Inflammation Unit, Integrative Neuroscience Department,

National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA

ACS Paragon Plus Environment

ACS Pharmacology & Translational Science 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract Traumatic brain injury (TBI) is becoming an increasing public health issue. With an annually estimated 1.7 million TBIs in the United States (U.S) and nearly 70 million worldwide, the injury, isolated or compounded with others, is a major cause of short- and long-term disability and mortality. This, along with no specific treatment, has made exploration of TBI therapies a priority of the health system. Age and sex differences create a spectrum of vulnerability to TBI, with highest prevalence among younger and older populations. Increased public interest in the long-term effects and prevention of TBI have recently reached peaks, with media attention bringing heightened awareness to sport and war related head injuries. Along with short-term issues, TBI can increase the likelihood for development of long-term neurodegenerative disorders. A growing body of literature supports the use of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor (R) agonists, along with unimolecular combinations of these therapies, for their potent neurotrophic/neuroprotective activities across a variety of cellular and animal models of chronic neurodegenerative diseases (Alzheimer’s and Parkinson’s diseases) and acute cerebrovascular disorders (stroke). Mild or moderate TBI shares many of the hallmarks of these conditions; recent work provides evidence that use of these compounds is an effective strategy for its treatment. Safety and efficacy of many


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incretin-based therapies (GLP-1 and GIP) have been demonstrated in humans for the treatment of type 2 diabetes mellitus (T2DM), making these compounds ideal for rapid evaluation in clinical trials of mild and moderate TBI.

Keywords: TBI, incretins, GLP-1, GIP, Gcg, glucagon, exendin-4, neurodegeneration, microglia, brain trauma Running Title: Incretin mimetics and TBI Graphical Abstract:

Introduction: Incretin Based Therapies- A Well Supported Approach to Traumatic Brain Injury Treatment Traumatic brain injury (TBI) constitutes a significant public health issue worldwide, increasing disability and mortality rates among all age groups.1 TBI ranges from mild (mTBI) to severe and presents diverse acute symptoms; the heterogeneity of the initial injury remains a barrier to the development of effective therapeutic interventions and clinical trials.2 The randomness of events leading to human head injuries requires a range of models that produce trauma analogous to that seen in incidents ranging from falls and sports related injuries to a severe car crash or explosion in war.3



The primary injury of TBI involves damage to brain tissue from direct trauma, typically in combination with inertial forces, with a secondary injury later emerging and characterized by widespread degeneration of neurons and glial cells.4 Secondary injury manifestations are delayed and suggest a possible therapeutic window.5 Pharmacologic intervention to reduce progression and severity of the secondary injury presents the greatest promise for counteracting a patient’s long-term morbidity and improving quality of life. Currently, there are no Food and Drug Administration (FDA) approved treatments for the secondary TBI injury6; instead there is much focus on symptomatic treatments of the condition, including those for headaches, sleep issues, fatigue, balance problems, and nausea.7 Other common acute manifestations of TBI include cognitive deficits in attention, learning and memory, and higher-order executive functions. However, these consequences can remain long after the initial injury.8,9 TBI can additionally lead to the development of chronic neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE).10–12 As Masel and Dewitt (2010)13 describe, TBI is “a disease process, not an event”, referring to a common practice among insurance agencies to classify TBI as a singular injury. The long-term consequences of the injury need to be considered following initial treatment.

Understanding of the molecular mechanisms underpinning the secondary TBI injury are important for the development of effective therapies for the mitigation of long-term consequences. Pharmacological treatments focused on the secondary and long-term neurological effects of the condition are currently emerging.14–20 Incretin mimetics are a particularly promising class of drugs for the treatment of mTBI and are based on the utilization of the endogenous incretin signaling system involving glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon (Gcg), and their receptors (R). GLP-1 and GIP exert similar mechanisms of action,21 and their longacting drug analogues were originally developed for their insulinotropic and insulin-sensitizing actions for the treatment of type 2 diabetes mellitus (T2DM), characterized by insulin resistance22,23 and blunted incretin effects.24 Incretin effects account for up to 70% of insulin release and defects in this system are thought to be main contributors to the development of T2DM.25 Endogenously, GLP-1 and GIP are chiefly produced in the small intestine and maintain low concentrations in the bloodstream26 that are rapidly upregulated in response to food ingestion. Following upregulation,


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GLP-1 and GIP act in a glucose-dependent manner on pancreatic -cells to stimulate the production and secretion of insulin and potentiate absorption of glucose by the body.

In contrast to the incretins, Gcg is most well-known for its action on the liver, stimulating the process of glycogenolysis, or the breakdown of glycogen into glucose. This lends itself to the effective treatment of severe hypoglycemia, or low blood sugar. GcgR antagonism has been explored as a way to effectively manage hyperglycemia. However, effects of GcgR agonism appear to play a pivotal role in satiety, metabolic homeostasis, and glucose metabolism.27 Clinically balancing combinatory levels of GLP-1, GIP, and Gcg in unimolecular incretin mimetics counteracts monotherapeutic problems, such as hyperglycemic liabilities of Gcg. Minor changes in peptide analogue sequences allow for longer acting pharmacological effects on receptors of interest.28 Endogenously, GLP-1, GIP, and Gcg are cleaved and inactivated by dipeptidyl peptidase-4 (DPP-IV) within two and eight minutes of their release.29,30 Resistance to this degradation is essential for incretin-based mimetics to effectively treat T2DM and other metabolic conditions (Figure 1).28,31



Figure 1. Amino acid sequences of incretins and glucagon and their mimetics

Figure 1. Amino acid sequences of incretin-based therapies. The discovery of the GLP-1 analogue Exendin-4 (commercially known as Exenatide), in the saliva of the Gila monster has paved the way for DPP-IV resistant incretin mimetics. Residue derivations for the dual- and tri-agonist incretin-based therapies are highlighted as well as resistance to DPP-IV cleavage. All endogenous human peptides are susceptible to DPP-IV cleavage while the mimetics display some form of resistance. Adapted from Tschöp et al. (2016).28

Incretin mimetics used in T2DM treatment are based upon the amino acid sequence of human GLP-1 and the naturally occurring analogue exendin-4 (Ex-4), which was originally isolated from the saliva of the Gila monster (Heloderma


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suspectum)32 and is resistant to degradation from DPP-IV consequent to a substitution of alanine (A) to glycine (G) in the 2-position of Ex-4 (Figure 1). These drugs have received increasing attention for their extrapancreatic effects, especially within the central and peripheral nervous system, as they have been shown to confer neurotrophic

33

and

neuroprotective actions in both in vivo and in vitro models of neurogenerative disorders.34–37 The recognition of a synergistic GLP-1/GIP or GLP-1/Gcg effect has led to the development of dual GLP-1/GIP and GLP-1/Gcg receptor co-agonists with the potential for enhanced efficacy than either mimetic alone.38–41 Recently, unimolecular combinations of GIP, GLP-1, and Gcg, have been shown to be a more physiologically balanced and amenable incretin combination for the diverse needs of human patients42 and show promise in several models of neurodegeneration.43 GLP-1 based polypharmacologic approaches to the treatment of metabolic diseases, and possibly neurological disorders, seem to hold much promise, as single therapeutics often have limited effectiveness.44 Alhough all commercially available GLP1R agonists are effective for diabetes treatment, head to head comparisons of clinical trials of each drug reveal differential ratios of reduced blood glucose and weight loss and the amount of adverse events associated with intake.45 No systematic comparisons of the effectiveness of T2DM treatment using dual and tri-agonists have yet been explored, although there are also likely differences in efficacy across these compounds as well. Understanding the residue contributions to the efficacy of these unimolecular combinations is difficult to assess, although the use of genetically modified mice with receptors of interest removed is an avenue to explore these questions.25 As Capozzi et. al (2018)25 point out, genetic deletion of these receptors has limitations and can potentially confound findings, as these mice may genetically compensate for these deletions and present atypical physiologic responses to the compounds.46 This leaves potential gaps in understanding of which mimetics to use in future clinical trials, especially for neurologic disorders. The amino acid sequences for GLP-1, GIP, Gcg, and their dual- or tri-agonist unimolecular combinations are shown in Figure 1.

Repurposing of the already well tested and tolerated incretin mimetics is promising for introduction to the general population for use in TBI treatment. Incretin mimetics have been shown to decrease neuroinflammation, excitotoxicity, oxidative stress, and apoptosis in animal models of a range of neurological maladies including autoimmune encephalomyelitis,47 retinal neurodegeneration,48,49 stroke,50–53 AD,54–57PD,58–63 and amyotrophic lateral sclerosis 64; all of these processes are also implicated in the progression of secondary TBI injury.65,66 Animal models of TBI have also



demonstrated efficacy of incretin and Gcg based mechanisms; some of the treatments used in these studies are FDA approved or in clinical trials (Table 1). More promising, improved outcomes in human clinical trials for PD67–70 and AD patients71 following treatment with GLP-1 analogues provide additional evidence for the safe use of incretin mimetics for the treatment of neurodegenerative conditions. Only two of the FDA-approved incretin-based mimetics used for the treatment of metabolic diseases, Bydureon®(AstraZeneca) and Victoza®(Novo Nordisk), have entered into clinical trials for the treatment of a neurological disorder, although newer drugs are also currently being explored for similar trials (Table 2). Sustained release formulations of incretins are becoming available and have been used in human models of PD67 and AD71 and animal models of AD,55 PD,60,72,73 and TBI.74 Recent studies of a unimolecular dual GLP1/GIP receptor co-agonist41 have shown therapeutic promise in animal models of mTBI75 (Table 1) and other neurodegenerative diseases.39,40,76,77 The latest iterations of incretin-based analogues utilize unimolecular GLP1/GIP/Gcg receptor tri-agonism42 and have been shown to provide neuroprotection in models of AD.78,79 These novel incretin mimetics likely provide similar neuroprotection and mitigation of neurodegeneration in models of TBI.


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Table 1. Incretin-based therapies in animal models of TBI

Table 1. Incretin-based therapies have been studied across a variety of TBI models of and have demonstrated efficacy in preventing apoptosis, oxidative stress, and inflammation, while providing neurotrophic support. GLP-1R agonism has been the most widely explored incretin-based therapy for TBI, though others have shown promise as well. FDA approved drugs and drugs in clinical trials are shown in red and blue respectively. SC=subcutaneous injection; Sources: a) 80; b) 81; c)82; d) 83; e) 84; f) 85; g) 86; h)87; i) 74; j) 88; k)89; l) 90; m) 75; n) 91




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Mechanism of Action

Company

AstraZeneca

Drug Name

GLP-1R/GIPR/GcgR Triagonist

Other Notes

Bydureon®

Once weekly SC

T2DM

2mg injection once each week, extended release formulation. Currently recruiting severely obese adolescents to participate in clinical trial (#NCT02496611). Phase 2 clinical trial (#NCT01971242) for PD patients completed ( See a. Athauda et al., 2017)

Byetta®

Twice daily SC

T2DM

Used any time within 1 hour before morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). In clinical trial (#NCT02442791) Neuroprotective effects of Byetta® administration following cardiac arrest showed no significant outcomes (See b. Wiberg et al., 2016). Phase 2 clinical trial (#NCT02838589) completed investigating effects on cerebral blood flow.

Lixisenatide

Adlyxin®/Lyxumia®

Once daily SC

T2DM

10 mcg once daily injection for 14 days. On Day 15, dosage increased to 20 mcg once daily. Administered within one hour before the first meal of the day.

Efpeglenatide

HM 11260C

Once weekly SC

T2DM

Currently recruiting patients for Phase 3 clinical trials (#NCT03353350, #NCT03496298)

GlaxoSmithKline

Albiglutide

Tanzeum®

Once weekly SC

T2DM

Once weekly at any time of day, irrespective of meals. Dosage can be increased from 30 mg to 50 mg for those that need.

Victoza®

Once daily SC

T2DM

Used at any time of day, independent of meals. Use 0.6 mg per day for one week then increase to 1.2 mg, which can be increased to 1.8 mg for additional glycemic control. Clinical trial in AD patients (#NCT01469351) completed in 2013 (See c. Gejl et al., 2016).

Saxenda®

Once daily SC

Weight Loss

Ozempic®

Once weekly SC

T2DM

NASH

Daily SC

NASH/NAFLD

-----------------

NN9926, NN9927

Oral

T2DM

Eli Lilly

Dulaglutide

Trulicity®

Once weekly SC

T2DM

Peptron

Exenatide SR

PT-302

Biweekly SC

T2DM/ PD

3 mg daily SC injection 0.25 mg (with or without meals). After 4 weeks, dose increased to 0.5 mg once weekly. Can be increased to 1 mg once weekly if needed.

Semaglutide Currently in Phase 2 clinical trials (#NCT02970942). NASH measurements are primary outcome with NAFLD as secondary outcome measure. Long acting, new molecular entities currently in development .75 or 1.5 mg SC injection once weekly from single dose pen Phase II clinical trials completed in South Korea for T2DM. Phase I clinical trial (#NCT00964262) completed for treatment of T2DM. Proprietary formulation allows for injection with smaller needle to reduce injection pain

Intarcia

Exenatide

ITCA 650

Long term implant

T2DM

Implant with potential to offer 6 month exenatide delivery with 1 year delivery options in development. Phase 3 clinical trials have been completed with New Drug Application (NDA) submitted to the Food and Drug Administration (FDA) (pending approval)

vTv Therapeutics

-----------------

TTP273

Oral once or twice daily

T2DM

Non-peptide GLP-1R agonist. Has completed Phase 2 clinical trial (#NCT02653599).

CSPC ZhongQi Pharmaceutical Technology Co., Ltd.

Recombinant Exenatide

rExenatide-4

SC twice daily

T2DM

Phase 3 Clinical trial (#NCT03239119) initiated, but not yet recruiting.

Oramed

Exenatide Oral

ORMD-0901

Oral

T2DM

US FDA cleared Investigational New Drug (IND) application for trials in humans as of September 2018.

Shanghai Biolaxy

Exenatide

Nodexen

Oral

T2DM

Nanoparticle oral delivery. Clinical trials ongoing in China.

Jiangsu Hengrui Medicine Co. Ltd.

Loxenatide

PEX168

Once weekly SC

T2DM

Clinical trials in progress (#NCT02477969). This formulation is PEGylated.

Neuraly Inc.

Exenatide

NLY01

Once weekly SC

PD/AD

Phase 1 clinical trial recruiting (#NCT03672604). This is a PEGylated formulation. See (d.) Yun et al., 2018

-----------------

GIP Peptide

-----------------

-----------------

T1DM

GIP peptide is currently recruiting for clinical trial (#NCT03556098) as a safeguard against hypoglycemia in patients with Type-1 diabetes mellitus (T1DM).

Zealand Pharmaceuticals

-----------------

ZP4165

Intra Venous (I.V.) or SC

T2DM

DPP-IV resistance and potentiates GLP-1 mediated weight loss and improved glycemic control in rats. See (e.) Nørregaard et al., 2018

Hamni Pharmaceuticals/ Janssen Research & Development, LLC

-----------------

HM12525A/ JNJ64565111

Once weekly SC

T2DM/Obesity

Zealand Pharmaceuticals/ Boehringer Ingelheim

-----------------

BI 456906

Once weekly SC

Obesity

Astra Zeneca/ MedImmune

-----------------

MEDI0382

Daily SC

T2DM

Sanofi-Aventis

-----------------

SAR425899

Daily SC

T2DM/Obesity

Clinical trials active (#NCT03414736). See (g.) Goebel et al., 2018

Janssen Pharmaceuticals

-----------------

JNJ-54728518

-----------------

T2DM/Obesity

Phase I clinical trials initiated for obesity and T2DM in 2016. Pre-clinical trials for obesity also initiated in 2016.

Novo Nordisk

-----------------

NNC9204-1177

Once weekly SC

Obesity

Currently recruiting for phase 1 clinical trial (#NCT03308721)

Prolor/OPKO Biological

-----------------

OPK-88003

Once weekly SC

T2DM

Currently recruiting for phase 2 clinical trial (#NCT03406377)

Spitfire Pharma

-----------------

SP-1373

Once daily SC

NASH/T2DM/ Obesity

Boehringer Ingelheim

-----------------

BI 456906

-----------------

Obesity

Eli Lilly

-----------------

LY3298176

Once weekly SC

T2DM

Completed phase 2 clinical trials (#NCT03131687). See (h.) Frias et al., 2018 for details.

Novo Nordisk

-----------------

RG 7697/NNC00902746/ MAR709

Once daily SC

T2DM

Completed phase 2 clinical trial (#NCT02205528). See (i.) Frias et al., 2017 for more details.

Sanofi

-----------------

SAR438335

Info not available

T2DM

Currently in Phase 1 clinical trials in France.

Novo Nordisk

-----------------

NNC9204-1706

Once daily SC

Obesity

Current Phase I clinical trial (#NCT03661879) recruiting.

Hanmi Pharmaceutical Co. Lmtd.

-----------------

HM15211

SC

Obesity

Long acting formulation. Current Phase I clinical trial (#NCT03374241) recruiting. See (j.) Kim et al., 2018 for latest research on compound.

Sanofi

-----------------

SAR441255

SC

Astra Zeneca

Saxagliptin

Onglyza™

Once daily oral

T2DM

Sitagliptin

Januvia®

Once daily oral

T2DM

25, 50, or 100mg with or without food.

Sitagliptin phosphate + metformin HCl

Janumet®/ Janumet®XR

Once daily oral (XR formula)/Twice daily

T2DM

Combination drug therapy with metformin. XR formulation is an extended release version. Max dosage 100mg Sitagliptin and 2000 mg metformin.

Omarigliptin

Marizev®

Oral once weekly

T2DM

Available in Japan. See (k.) Goldenberg et al., 2017 for phase 3 clinical trial information (#NCT01703221). Possible repositioning of drug for intranasal delivery for PD (l.) (Ayoub et al., 2018).

Trelagliptin

Zafatek®

Oral once weekly

T2DM

Approved for use in Japan. Phase II clinical trials abandoned in the USA because of costs.

Alogliptin

Nesina®

Oral once daily

T2DM

25 mg with or without food

Bristol-Myers Squib

Linagliptin

Tradjenta®

Oral once daily

T2DM

5 mg once daily

Dong-A ST

Evogliptin

Suganon®

Oral once daily

T2DM

5 mg once daily. Approved for use in South Korea in 2015. Sold with extended release metformin.

SatRx LLC

Gosogliptin

SatRx®

Oral

T2DM

Approved for use in Russia. Completed Phase 3 clinical trial of safety alone or with metformin compared to Vildagliptin alone or with metformin #NCT03088670.

LG Life Sciences/ Sanofi

Gemigliptin

Zemiglo ™

Oral once daily

T2DM

Long acting DPP-IV inhibitor. See (m.) Kim et al., 2016 for characterization.


Vildagliptin

Galvus®

Oral once daily

T2DM

50 mg in combination with metformin. See (n.) Mathieu & Degrande, 2008

Mitsubishi Tanabe Pharma and Daiichi Sankyo

Tenegliptin

Tenelia®

Oral twice daily

T2DM

20 mg twice daily. See (o.) Kishimoto, 2013


Anagliptin

Suiny®

Oral twice daily

T2DM

Approved for use in Japan, 200 mg daily. See (p.) Nishio et al., 2015

Merck

Takeda

DPP-IV Inhibition

Latest formulation of Bydureon®

Sanofi-Aventis

Novo Nordisk

GLP-1R/GIPR Dual Agonist

T2DM

Sanofi-Aventis/Hanmi Pharmaceuticals

GLP-1R Agonist

GLP-1R/GcgR Dual Agonist

Uses

Once weekly SC

Exenatide

Liraglutide

GIPR Agonist

Administration

Bydureon®BCise™

Currently recruiting for phase 2 clinical trials (#NCT03586830). Long lasting analogue of amylin and partially builds on the effects of oxyntomodulin. Initiated Phase 1 clinical trial (#NCT03175211) in 2017 to assess safety, tolerability, and pharmacokinetics/pharmacodynamics. Phase I trials in Germany for obesity initiated. Completed phase 2a clinical trials (see f. Ambery et al., 2018). Phase 2b clinical trials underway (#NCT03235050).

Clinical trial for T2DM and obesity planned for 2019. Currently recruiting for Phase 1 clinical trials (#NCT03591718).

T2DM/Obesity/ Preclinical NASH 2.5 or 5mg regardless of meals

Table 2. Incretin-based therapies approved for use or in clinical trials Table 2. There are currently a wide variety of incretin-based therapies approved for the treatment of metabolic diseases (shown in red and green if approved in the USA or elsewhere respectively) and many more that are in clinical trials or development (shown in blue). Included in this table are the DPP-IV inhibitors which increase endogenous levels of GLP-1, GIP, and GCG. Formulations of incretin based therapies in clinical trials focused on neurological diseases are highlighted in yellow. Bydureon® and Victoza® are the only FDA approved incretin analogues that have completed clinical trials for a neurological disease/disorder. There are currently no GIPR-GCGR antagonists under investigation. #: Clinical trials can be found at https://clinicaltrials.gov . NASH=Nonalcoholic steatohepatitis; NAFLD= Non-alcoholic fatty liver disease; SC= subcutaneous injection; T1DM= Type 1 Diabetes Mellitus. Sources: a) 67 b) 92 c) 71 d) 93 e) 94; f) 95; g) 96; h) 38; i) 97; j) 43; k) 98; l) 99; m) 100; n) 101; o) 102; p) 103



Traumatic Brain Injury: A Public Health Perspective The United States Center for Disease Control’s (CDC) analysis of 2013 health care data finds that there were approximately 2.5 million TBI-related emergency department (ED) visits, 282,000 TBI related hospitalizations, and 56,000 TBI associated deaths,104 all increases from previous estimates.105 Although hospitalizations related to TBI have remained consistent, TBI-related visits to the ED have escalated dramatically. Between 2007 and 2013 there was a 32% increase in overall TBI-related ED visits,104 further corroborated by two other separate analyses showing significant upsurges in TBI related ED visits between 2006-2010 106 and 2007-2010.107 The 2006-2010 analysis found a 56% rise in TBI-related hospitalizations, despite only a 3.6% increase in total ED visits. Increased public awareness of TBI, specifically of mild forms, has likely led to this rise in ED visits.106 Increases in TBI-related ED visits include those associated with sports injuries, which saw a 65.9% rise in annual visits between 2006 and 2011 (65,516 to 105,384 annual visits).108

Epidemiological analyses of these trends is difficult to assess, although a similar conclusion can be made from them all: TBI remains a significant health issue for millions of people, both immediately following the injury and in the years and decades following. Estimates indicate approximately 3.2109 to 5.3 million110 Americans are currently living with a long-term disability associated with a TBI incident, albeit these estimates likely underestimate actual incidence due to underreporting from those sustaining a TBI and the lack of high quality monitoring data.11,111 Long term outcomes following a pediatric TBI are especially difficult to assess.

Children, especially boys, are highly vulnerable to TBI.112

Boys are less likely to wear head protection and are more likely to be injured deliberately causing much of the injury disparity compared to girls.113 Whereas much of the general public’s focus and interest in TBI stems from sports-related injuries, elderly individuals’ falls are most associated with the increases in TBI-related ED visits.104 The elderly population has lower thresholds of injury severity that result in higher mortality and worse functional outcomes than younger individuals.114,115 This, combined with higher medication use and comorbid conditions, exacerbate poor outcomes in the elderly.104 Globally, TBI’s result in over 10 million deaths per year. It is not currently known how many individuals are living with a disease/disability resulting from a previous TBI, but approximately 60 million individuals worldwide have previously been hospitalized for TBI-related injuries.110


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Military personnel remain at high risk for TBI. The Global War on Terrorism in the Middle East and ongoing military operations in Iraq and Afghanistan have spanned 16 years and have involved more than 2.7 million U.S. and coalition personnel.116 TBI is referred to as the “signature wound” of the ongoing military conflict due to the higher rates of these injuries than in prior conflicts. United States personnel TBI cases are in addition to many more cases in enemy combatants and the unfortunate innocent citizens of the countries in which the combat has occurred. Blast injury is the main cause of casualties and TBI, resulting from enemy combatants’ increased use of improvised explosive devices (IEDs), rocket-propelled grenades, and landmines. Estimates range from approximately 15%117 to 19.5–22.8% of all returning deployed US troops118,119 having suffered a blast exposure TBI, with total cases of military related TBI injuries between the years 2000-2018 reaching greater than 383,947.120 For this assessment, only the highest severity injury was recorded for individuals who sustained more than one TBI. Based on the updated 2015 version of the International Classification of Diseases121 (Figure 2A), roughly 82% of all military related TBIs between 2000 and 2018 can be classified as mild.120

Diagnosis of blast induced TBI is often delayed. Military personnel are 8.4 times more likely to be diagnosed with a TBI within four weeks following return from deployment than before entering combat.122 Chances of a TBI diagnosis remain heightened for over a year, with reasons ranging from a lack of recognition or underreporting of experiencing high-risk events by those injured during combat to riskier behaviors upon return home.122,123 Long term outlook for military personnel diagnosed with an mTBI have shown increased risks for developing PD124 and dementia125 years after initial injuries. Commonly referred to as “shell shock” or “post-concussion syndrome” during World Wars I and II, closed head injuries related with proximity to explosions resulted in symptoms including amnesia, concentration issues, headache, and dizziness. During these wars, debate on whether these symptoms were of psychological or physical manifestation were unclear126; however, scientists now understand clear physical connections between injuries from blast exposure and many of the symptoms observed.127

Increasing evidence suggests that both single and repetitive TBI injuries can lead to the development of neurodegenerative diseases with possible dose- and frequency-dependent correlations11,128; however, genetic predisposition and environmental factors likely play a key role in the threshold for clinical manifestation.129–133 Moderate



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and severe TBIs require high levels of monitored care, although mild injuries can also result in long-term deleterious health effects. In addition, cognitive deficits and behavioral or emotional changes such as irritability, poor memory, attention, and depression may manifest.134 Whereas many symptoms of mTBI may resolve rapidly, deficits can be evident years later, often unattributed to the initial injury. Figure 2. Basic TBI Diagnostic Assessment in Military and General Clinical Settings

A Structural Imaging Duration of lost consciousness Duration Confusion/Disorientation Duration of Memory Loss

Mild

Moderate

Severe

Normal

Normal to Abnormal

Normal to Abnormal

0-30 mins

>30 min and < 24 hours

0-24 hours

>24 hours + Additional criteria applied to these cases in determining severity.

0-24 hours

>1 Day and 24 hours

Glasgow Coma Scale RESPONSE

SCALE

Eye opening response

Spontaneously To speech To pressure No response Oriented to time, place, and person Confused Inappropriate words Incomprehensible sounds No response Obeys commands Moves to localized pain Flexion withdrawal from pain Abnormal flexion Abnormal extension No response Mild TBI Moderate TBI Severe TBI

>7 Days

Figure 2. Classifying severity of a TBI is the first step in determining treatment options and trajectory. Basic diagnostic categorization used in a military context is shown in (A). With increasing use of blood-based biomarker surveillance, the use of brain imaging across each severity level will likely be highlighted less and perhaps deemed unnecessary for all cases. The Glasgow Coma Scale (GCS) (B) is a widely used diagnostic tool in assessing the severity of TBI, though the medical community is currently improving on less subjective readouts to better diagnose level of injury and needs of each patient. (A) was adapted from Defense and Veterans Brain Injury Center (2015)121 and (B) from Teasdale et al. (2014).135

Verbal response

Motor response

Total score

SCORE 4 3 2 1 5 4 3 2 1 6 5 4 3 2 1 13-15 9-12 3-8

Although much of the mystery surrounding the long-term effects of TBI remain today, advances in diagnostic metrics and severity assessments have the potential to change disease outlook and treatment options. Since the 1970s, diagnosis of TBI severity has relied on using the Glasgow Coma Scale (GCS), which scores patients’ ability to open eyes, respond verbally, and perform a motor response135 (Figure 2B). Scores range from 3 to 15, with lower scores associated with the most severe TBIs and higher scores with injuries considered moderate or mild. Even though it is an easy to use tool for TBI diagnosis and potential prognosis, the GCS does not provide objective readouts underlying patient specific pathophysiological sequalae that underpin such diverse outcomes 2, especially with regard to severe trauma in elderly patients.136,137 New technologies in brain imaging134 and blood biomarker surveillance138–140 are in rapid development and will likely be standardized in the near future. This will be particularly helpful for long term diagnoses and potentially be used for early identification of secondary disease manifestations such as the that of CTE.141 Use of blood biomarkers remains in its relative infancy, with the FDA approving the first blood test for TBI patients in 2018.142,143 A quick turnaround is clearly essential for these tests to be effective, and once standardization is achieved, this will represent a shift to biological readouts to diagnose TBI, instead of or in combination with the commonly used, and still useful, GCS. Moreover, simple blood tests may potentially decrease the costs of healthcare


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by decreasing the needed number of procedures such as head scans for many mTBIs.

Mechanisms of TBI Damage Despite the diversity of TBI cases and their outcomes, all CNS trauma pathology is determined by primary and secondary phases of injury. Immediately following a contusion; primary injury includes mechanical force damage to the brain that can rapidly cause neuronal cell necrosis (limited to the epicenter in mild cases), axonal injury, disruption of the blood brain barrier (BBB), reactive oxygen species (ROS) release, and spreading excitatory neurotransmitter release and depolarization65,144 (Figure 3A). A hallmark of diffuse TBI is axonal damage, with visible degeneration of white matter tracts, as evidenced in CT and magnetic resonance imaging (MRI) brain imaging studies.145,146 Stretching and shearing of cell membranes from TBI cause rapid sodium and calcium ion influx into neurons, resulting in cell membrane depolarization.147 Shortly after the primary TBI injury, neutrophils arrive to contain the damage by removing cellular debris and damaged cells, although their action can also have pathogenic effects, especially in more severe TBIs.148 In events such as TBI, damaged neurons undergoing non-apoptotic death release danger-associated molecular patterns (DAMPs), including S-100 proteins and other alarmins149,150, into the extracellular space where they can activate cytokine and pattern-recognition receptors (Figure 3B). Activation of these receptors, including purinergic and toll-like receptors (TLRs), especially on astrocytes and microglia, initiates an inflammatory response.151

Microglia are the resident macrophages of the brain and are endowed with highly motile processes that survey the brain for damage and maintain homeostasis.152 DAMPs inform an immune reaction that cause a phenotypic shift in microglia from a resting or “surveying” state in to an “activated” pro- or anti-inflammatory state, traditionally referred to as M1 and M2, respectively153 (Figure 3C). However, this commonly used dichotomous nomenclature does not fully encompass the phenotypic diversity of microglia,154 further supported by recent single cell RNA-sequencing of microglia throughout the mouse lifespan and following injury155 as well as characterization of region-specific genetic diversity in mice156 and rats.157 Indeed, previous studies have shown varied activation states of microglia across a wide variety of models of TBI,158 although a more thorough investigation of the diversity of microglia populations following this acute insult is needed. Markers of general microglia activation include antibodies to ionized calcium-binding adaptor molecule 1 (Iba-1) and/or some combination of others such as CD68 or CD11b.159 A recent murine-based study found that



following mTBI-induced disruption of the BBB, there is damage to the glial limitans - a barrier of astrocytic GFAPpositive endfeet tiling nearly all cerebrovascular basal lamina and that is central to the selective permeability of the BBB - resulted in a purinergic receptor-dependent recruitment of microglia to support or replace the damaged astrocytes. These microglia formed a phagocytic barrier, preventing further leakage into the brain parenchyma and provided neuroprotection early in the injury.144 This is just one example of the many roles of microglia during a traumatic pathological event. Regardless of the current microglial heterogeneity debate, chronic activation of microglia is a hallmark of secondary TBI injury in humans. This has been demonstrated up to 17 years post-TBI in vivo146 and in postmortem tissues.160 Inflammation can persist years after a single TBI event in humans,160 and animal models of TBI show chronic microglial activation as a primary mechanism for TBI secondary injury and CNS deficits.161,162 Chronic microglial activation in the thalamus, remote to the focal injury, is closely related to the amount of thalamocortical damage.146 Preliminary evidence in human TBI patients indicates a correlation between increased chronic thalamic microglial activation and greater cognitive deficits.146 Furthermore, diffusion tensor MRI studies in humans support the hypothesis that damage to thalamico-cortical fiber tracts is a key factor underpinning deficits in executive function following TBI.163 Additional evidence comes from age-dependent upregulation of activated microglia in the thalamus in healthy individuals and in several cortical regions in humans with AD.164

Microglia in brains of people subjected to insult, injury, or disease, as well as microglia in aging, are often found to be in a “primed” state; that is, microglia that express a pro-inflammatory gene profile and exhibit a hyper-reactive inflammatory response to subsequent disturbances when compared to naïve cells.165–167 Such priming of microglia is also thought to contribute to long-term effects of even a singular TBI event. Subsequent TBIs exacerbate the inflammation response in these cells166,168 (Figure 3F). In addition, chronically activated microglia interact with neurons, removing excess synapses169,170 and release higher basal levels of cytokines.168,171 In animal models of brain injury and aging, Kim Green and colleagues have experimented with “resetting” the microglial phenotypic profile by pharmacologically (via colony-stimulating factor 1 receptor inhibition) ablating primed microglia and repopulating them via drug withdrawal. Microglia-depleted mice experience no behavioral deficits,172 and when repopulated following injury or in aging models, microglia are morphologically naïve. These animals experience decreased inflammation profiles, rescued behavioral outcomes, and increased dendritic spine numbers.173 Aged mice with repopulated microglia


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show similar microglial densities, morphologies, and overall gene expression profiles as those of young adults, with increased neuronal function and reversal of impairments in long term potentiation (LTP).170 Though responses to inflammatory stimuli remain unchanged in the repopulated microglia, these improvements are notable. Importantly, this reveals links to long-term deleterious implications of primed microglia involvement in chronic neurodegeneration and the aging process. Another recent study corroborates Elmore et. al (2018)170 with findings that microglial repopulation in aged mice reverts microglial phenotypes but does not change responses to subsequent inflammatory stimuli; deleterious environmental cues such as astrocyte activation remain after repopulation and contribute to hyper-reactivity of the new microglia.174 Microglia depletion and repopulation therapies have been tested successfully across a wide range of animal models.175 Only recently has this therapy been utilized in a TBI model, reducing both inflammationrelated gene profiles and astrogliosis following injury.176 Future research is needed to show cognitive effects of microglia replacement following TBI.

Shortly after a TBI, cytokine and chemokine protein expression are upregulated.177 This orchestra of proteins includes CCL2, CCL20, CCL21, Il-1, IL-1, IL-6, IL-10, TNF-, IL-8, iNOS, MHCII, IL-12p40177–179 and the complement cascade (including C1q and complement component 3 (C3)).180–182 These proteins facilitate a panoply of both deleterious and restorative processes179 and can act in a paracrine or autocrine fashion. Increased C3 active fragments are observed in human TBI patients.181,182 In mouse models, pharmacological inhibition of C3 active fragment formation183 and C3 knock out (KO) mice184 provide neuroprotection following TBI. Release of Il-1, TNF-, and C1q by activated microglia is sufficient to induce the formation of neurotoxic A1 astrocytes that produce a neurotoxin capable of inducing rapid death of subsets of neurons and oligodendrocytes185 (Figure 3D). This so called “A1” astrocyte profile, characterized by high C3 protein expression (among others), is prevalent in normal aging186 and chronic neurodegenerative diseases such as PD, AD, ALS, and HD.185 Normally aged triple-KO mice (mice that do not produce Il-1, TNF-, and C1q) have significantly reduced A1 gene profiles,186 highlighting a role for primed microglia in the development of this cell phenotype in normal aging. Microglia depletion therapy in mice prevented TBI-induced increases of IL-1 and C1q and downstream astrogliosis.176 There is increasing interest in the role of C3 and the complement cascade in the exacerbation of secondary injury and chronic neuroinflammation following TBI.180 Recent work shows that targeted inhibition of C3 activation in a controlled cortical impact (CCI) TBI model improves cognitive recovery and inhibits



chronic neuroinflammation and neurodegeneration.187 Furthermore, aged C3 deficient mice lack age-related neuronal functional deficits in the hippocampus,188 and pharmacologic or genetic inhibition of the complement pathway following TBI in aged mice prevents cognitive deficits.189 The acute inflammatory environment immediately following a TBI and the long term elevation of TNF- from primed microglia may, likewise, be implicated in impaired memory via altered astrocyte activity and signaling,190 again highlighting the importance of understanding the crosstalk between multiple cells types following brain trauma. It is important to note that the inflammatory response is not wholly adverse. For example, inflammatory mediators such as TNF- also induce CNS repair. In a TBI model using transgenic mice that did not produce TNF-, wild type mice recovered motor function faster and experienced less cortical tissue loss from the injury.191

Figure 3. Mechanisms of TBI damage

Figure 3. Depending on severity, the primary TBI injury is scaled in the focal region and includes disruption of the blood-brain barrier (A) and direct injury to cells (B). This can result in cell death and release of intracellular contents including neurotransmitters, ROS, and other cell debris which act upon surrounding cells in a cascading fashion. Microglia phagocytize cell debris and detect damage signals that result in increased Iba1 expression, phenotypic shifts, and altering roles for microglia (C). M1 microglia act in a pro-inflammatory manner, releasing cytokines and chemokines that act in a paracrine and autocrine fashion alerting surrounding cells that damage has occurred. This initiates recruitment of other cells to respond. M2 microglia maintain a phagocytic role and continue to clear cell debris and release anti-inflammatory cytokines. DAMPs from damaged cells and cytokines released from M1 microglia, including Il-1, C1q, and TNF-, act upon resting astrocytes and initiate the formation of reactive astrocytes, most commonly characterized by increases in GFAP expression (D). A2 astrocytes are theorized to be reparative and maintain a phagocytic capability, clearing damage, while A1 astrocytes lose this ability and produce an unidentified neurotoxin that acts on surrounding neurons. Following TBI, astrocytes have decreased capability to transport free glutamate. This, compounded with cytokine, specifically TNF- and IL-1, initiated increases in glutamate production in neurons and the


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activation of glutamate receptors from excess interstitial glutamate, causes a classic excitotoxic response that damages healthy neurons and eventually can lead to cell death (E). Microglia affected during the TBI injury or secondary phase of the injury may become chronically activated with an overall increased pro-inflammatory profile (F). These cells are hyper-reactive to inflammatory stimuli (including subsequent TBIs) and have been implicated in the progression of long-term neurodegeneration and related diseases.

Astrocytes respond to pro- and anti-inflammatory cytokines in a “context-dependent” manner that allows for a diverse range of phenotypic subtypes.192 These “reactive astrocytes” have traditionally been characterized by increased GFAP expression193; however, increased GFAP expression is not limited to the A1 variety194 (Figure 3D). Indeed, GFAP is an important marker for TBI pathology, as upregulated levels of astrocyte-derived GFAP in the blood serum of TBI patients is recognized as an accurate indicator of TBI severity.143 Though not fully understood, GFAP serum levels in older patients may not be as accurate an indicator of TBI as in younger patients.195 Although the biological role of the “neurotoxic” A1 astrocytes is not well-defined, this population is clearly involved in the neurodegenerative process. Importantly, such a role is not exclusive amongst astrocytic involvement in TBI. Participation of other inflammationinduced subtypes of astrocytes, such as the “A2” variety,194 appear to play crucial roles in mitigating TBI pathology by providing neuroprotection via a variety of mechanisms.192,196 In synopsis, glial cells appear to take on many different activities during pathological events, and it is the balance between these that ultimately defines the final outcome.

Excitotoxicity is a common pathological feature of secondary TBI injury arising from excess extracellular glutamate, the prominent excitatory neurotransmitter171,197 (Figure 3E). Regional microdialysis studies have reported elevations of glutamate immediately following TBI that appear to depend on both injury severity, with a prolonged elevation in severe traumas, and the number of physiological variables involved.198–200 Astrocytes are largely responsible for the uptake of extracellular glutamate via glutamate transporters201 and following TBI, decreased expression of these transporters in astrocytes has been demonstrated in animal models202 and in humans.203,204 Astrocytes205,206 and microglia207,208 responded to TNF- by amplifying glutamate release. TNF-, together with Il-1, increases neuronal production and release of glutamate, further escalating extracellular levels of the neurotransmitter209 (Figure 3E). Research describing the role of TNF- in mediating excess interstitial glutamate is growing, and there is extensive interest in using drugs to reduce this cytokine’s activity across a wide variety of CNS conditions and injuries.210,211 Excess glutamate leads to overstimulation of postsynaptic glutamatergic receptors, specifically the N-methyl-D-aspartate receptors (NMDARs) and 2-amino-3-[3-hydroxy-5-methylisoxazol-4-yl] proprionate receptors (AMPARs), which allow calcium entry into cells



and causes neuron depolarization and further glutamate release.212 Overstimulation of these receptors leads to intracellular ionic imbalance, with excess calcium playing important roles initiating intracellular cascades and cell damage (Figure 3E). Altered calcium homeostasis can lead to calcium-dependent cysteine protease, or calpain, activation which amplifies pro-apoptotic signaling, including activation of BID, BAX, and p53, while decreasing antiapoptotic Bcl-2 protein. This leads to neuronal dysfunction and apoptosis,213 and at very high levels of calpain activation, necrosis can result.214

In response to elevated levels of ROS and subsequent DNA damage during TBI, overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) may result and is associated with depletion of cellular energy stores and necrosis.215 PARP-1 inhibition shows improved outcomes in animal models of TBI216–218 (Table 3) and increased expression of PARP-1 has been demonstrated following human TBI

219.

Along with its involvement in microglial activation,217,220,221 PARP-1

promotes the mitochondrial release of apoptosis inducing factor (AIF) and its carrier protein cyclophilin A (CypA).222,223 AIF is then translocated to the nucleus where it initiates chromatin condensation, DNA fragmentation, and ultimately cell death223 (Table 3). Uniquely, this cell death pathway is caspase independent.222 Additional cell death mechanisms can involve the initiation of cell-cycle activation (CSA). Neurons are postmitotic cells though CSA pathways may be reinitiated from oxidative stress and DNA damage induced from TBI or other insults.224,225 This is supported by increased expression of the CSA markers cyclin D1, CDK4, E2F5, c-myc, and PCNA and downregulation of cell cycle inhibitors following TBI.226 Genetic or pharmacologic inhibition of CSA in animal models of TBI show decreased cell death, glial activation, lesion size, and improved cognitive recovery227–229 (Table 3).

Following even mild cases of TBI, apoptotic pathways rise acutely and are sustained in the long-term.230 Hyperactivity in neurons and decreased blood flow to the focal injury leads to increased metabolic stress and subsequent depletion of adenosine triphosphate (ATP) stores. This may cause high levels of ROS which can lead to cell death.231 Within neurons, the transcription factor p53 is activated and results in delayed apoptotic cell death in the subacute period after TBI (as well as in response to oxidative stress, glutamate excitotoxicity and other insults). In a CCI model of TBI in mice, p53 levels were found to be elevated in the brain as early as 15 minutes after the TBI procedure and timedependently rose and was sustained over time.232 At 5 hours after TBI, a robust increase in p53-labeled cells was evident within the site of maximal CCI injury in the brain

233.

Stable inhibitors of p53 (Table 3), Pifithrin-α (PFT-α) and


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analogues234,235, have been shown to minimize apoptotic cell death by inhibiting p53 transcriptional activity and preventing p53-dependent activation of apoptotic pathways.236,237 This is also purported in rodents challenged with CCI-induced moderate TBI20,232,233,238 as well as weight drop-induced mild TBI,18 resulting in substantial mitigation of ensuing neuronal loss and cognitive deficits with a therapeutic window of 5 to 7 hours after injury. These studies clearly demonstrate that the secondary TBI phase of cell death involves apoptosis and that post-TBI inhibition of apoptotic mechanisms can mitigate the associated deficits. Whereas PFT-α and analogues are pharmacological tools to inactivate p53-dependent pathways; importantly, approved classes of drugs can likewise prevent neuronal p53dependent apoptosis without the potential concerns of globally blocking p53 activity. In addition to transactivation of multiple apoptotic gene pathways within the nucleus, p53 also mediates apoptosis by binding and inactivating the antiapoptotic proteins Bcl-xL and Bcl-2 on the mitochondrial surface and directly activating the apoptotic proteins Bak and Bax. Mitochondrial p53 translocation induces mitochondrial outer membrane permeabilization (MOMP) via Bak and Bax, release of mitochondrial proapoptotic factors (e.g., cytochrome c, Smac/DIABLO, PUMA, and AIF) into the cytosol, and subsequent activation of caspase 3-dependent apoptosis.234,236,237,239,240 A thorough summary of the effects of various genetic and pharmacologic disruptions of cell death pathways following TBI is shown in Table 3.

Table 3. Pharmacologic or Genetic intervention of Cell Death Pathways in TBI

Pharmacologic or

TBI Model/Outcome

Genetic Intervention Caspase-8 -/-



CCI: Reduced injury size, apoptosis, reduced caspase-3 processing241

Caspase



CCI + secondary insult: Reduced contusion size, caspase-3 activity and DNA

inhibitors

fragmentation but no functional benefit 242 

FPI: Improved motor and spatial learning243



CCI: Improved motor and cognitive function244



CCI: No improved functional or histological outcomes but reduced caspase-3 activity and cytochrome c expression245

Cyclin D1 -/-



CCI: Reduced cell cycle activation, decreased lesion volume and microglial activation 228

Cell Cycle inhibitors



FPI: Decreased neuronal cell death, lesion size, glial activation, and improved cognitive recovery227





FPI: Decreased glial activation, oxidative stress, neuronal cell loss, and improvements in cognitive function229

p53 -/-



Improved neuromotor function (cell loss not attenuated)246

p53 inhibitors



CCI: Reduced lesion size and inhibition of NF-B232



CCI: Decreased contusion volume, apoptosis, protection from glutamate excitotoxicity233



CCI: Improved motor deficits and memory and decreased apoptosis and apoptosis related gene expression238



CCI: Improved motor deficits and reduced oxidative damage, glial activation, inflammation, and apoptosis20

PARP -/-



CCI: Improved motor and memory function but no effect on contusion volume218

PARP-1 inhibitor



FPI: No effect on TUNEL-positive apoptotic cells but significantly reduced lesion size247



CCI: Decrease neuron death, microglial activation, and neurological deficits217



CCI: Reduced inflammation and glial cell activation220



CCI: Decreased neuronal cell death248

CypA -/-



CCI: Reduced apoptotic cells and improved motor and cognitive recovery222

Bax Inhibitor-1



CCI: Reduced brain lesion volumes and improved motor performance249



CCI: Reduced lesion volume in cortex and hippocampus with reduced glial cell

AIF deficient (hqhom)

Tg Bcl-2 Tg

activation250 

CCI: Reduced lesion volume. No effect on composite motor scores or hippocampal death251

CCI: Decreased early cell death and tissue damage but no effect on functional outcome

Bid -/-



Bax -/-



CCI: Improved neurogenesis and increased neural progenitors253

TNFR -/-



CCI: Reduced cortical lesion volume and improved BBB integrity254

MnSOD Tg



CCI: Reduced cortical lesion volume and improved BBB integrity254

deficits252

Table 3. Evidence for mechanisms of cell death in TBI are shown from pharmacologic (red) or genetic (green) disruption of these pathways. Included are transgenic (Tg) and knockout (-/-) animals of relevant cell death pathways. Effects of these interventions following TBI are shown on the right. Adapted from 255. CCI= Controlled cortical impact; FPI= Fluid percussion injury; hqhom= Homozygous Harlequin mice

Animal models of TBI Significant heterogeneity across the spectrum of clinical TBI subtypes necessitates a wide range of models to mimic aspects of human injury. Although similar GCS scores may indicate similar levels of injury, the appearances of those injuries can vary widely, including the presence of hematomas, cerebral contusions, pneumocephaly, hemorrhaging, and subdural hydromas,256 or none of these at all. A wide range of models of TBI are necessary to evaluate the random nature of the injury. Although larger animals have been used in modeling TBI,257 their expense and ethical concerns


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have shifted the scientific community to primarily use rodents for these studies. Arguments for the use of larger animals in these studies cite differences in the size and structure of rodent brain compared to human (lissencephalic versus gyrencephallic), clinically relevant monitoring ability (intracranial pressure, brain tissue oxygen content, and cerebral blood flow), and possible differences in mechanisms of repair.257,258 The body of work using rodent models continues to grow due to the low cost, standardized methodologies, especially regarding behavioral testing, and ease of manipulating complex molecular cascades via pharmacologic or genetic means255,259 (See Table 3). Focus on animal models that resemble mild human head injury is essential, as a majority (>70%) of human TBI’s are classified as mild.260

The most commonly used models include the weight drop (WD) method, controlled cortical impact (CCI), and fluid percussion injury (FPI), and more recently models of blast TBI to understand the large number of TBI cases from military personnel (all reviewed extensively).3,259 Although rodents are primarily used in these models, they are amenable to larger specie.3 The CCI and FPI models require removal of a piece of skull (craniectomy in CCI and craniotomy in FPI) in a region of interest and are defined by a controlled pressure pulse initiated by either the tip of a rod attached to the CCI device or a pendulum striking a piston attached to a reservoir of fluid for the FPI device. Albeit the direct impact onto the dura and method of injury makes these models not completely analogous to common head injuries seen in humans, they are particularly effective at consistent and graded injuries.3 The WD and blast models of TBI both utilize closed head injuries whereby a weight is dropped through a cylindrical tube of a predetermined height (such as 80 cm) and onto the head of an anesthetized mouse or the anesthetized mouse is exposed to some variation of blast waves from a controlled open-field explosion of TNT.3 Due to the limitations and danger of explosives, increased use of “shock tubes” that use compressed gas to deliver shock waves are expanding the research of blast TBI.261 These injury models closely resemble common clinical cases of TBI incurred through falls, sports injuries, traffic accidents262 or on the battlefield.261

The use of standard behavioral assays in rodent models are valuable for understanding cognitive deficits in human TBI, often considered a silent symptom of the condition. WD, CCI, FPI, and blast TBI models all demonstrate cognitive deficits (cited in Table 4). This is manifested in a neurological severity score (NSS), which combines behavioral and motor function performance tests (see 254), or in some cases, more simplified behavioral assays of memory such as



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the novel object recognition (NOR) or Y-Maze spontaneous alteration tests.3 Previous WD based studies confirm the visual memory deficits demonstrated by the NOR test at 7 and 30 days post-TBI,81,84,264–266 although memory deficits demonstrated via the Y-maze are often evident but not as consistent across these same studies. This highlights the heterogeneity across mTBI injury and potential inconsistency in delivery of the TBI, which is in line with the human condition where no two TBI events are identical. Depressive effects of mTBI are evaluated by the forced swim test and have been observed 7 days (for the 70 gram WD) and 30 days (50 and 70 gram WD) post-TBI. This is notable, as depression is a common symptom in human TBI patients.267

Table 4. Observed effects following animal models of TBI Iba1/ Microglial Activation

GFAP/ Astrocyte Activation

WD

74, 268–270

74, 265, 271, 272

Blast

286, 287

FPI

176, 229, 299,

176, 227,

176, 299, 302,

229, 299, 303,

229, 299,

300

229, 301–

304, 305

305, 306

303, 305,

CCI

161, 220, 319–

20, 320, 323

20, 322, 324, 325

228, 244, 324

20, 242, 245,

20, 228, 242, 244, 245,

249, 324

249, 321, 326, 327

288–292

Cytokine Elevation

Cognitive Deficits

Apoptotic Signaling

Cell Death/ Neurodegeneration

Synaptic Plasticity/ Function

BBB Integrity

Oxidative Stress

Glutamate Regulation

74, 264, 265,

18, 19, 74, 84,

18, 232, 265,

18, 74, 265, 280

281, 282

283, 284

19, 277

19, 285

268, 270, 271,

264, 265, 275–

276, 279 86, 286, 293

87, 297, 298

287, 296

287, 290, 292–

292

273, 274

278

293, 294

86, 87, 293, 295

286, 292, 296

303 324

294, 296 301, 306–309

310–312

302, 308, 313

229, 303, 312,

309, 315–318

314

306 327, 328

85, 326, 329,

20, 321, 324,

330

326, 327, 331

198, 332–334

Table 4. The weight drop (WD), blast, fluid percussion injury (FPI), and closed cortical impact models of TBI effectively model pathophysiological sequalae of TBI in humans. Differences in reproducibility and applicability to human injury should be assessed before using one model over another, as each model has its own positive features and caveats. BBB= Blood-brain barrier

In addition to assessing behavioral and motor outcomes, WD, CCI, FPI, and blast models of TBI demonstrate a wide variety of pathophysiological sequelae similar to human TBI including [a] neuroinflammation, epitomized by increased cytokine production and microglial (increased Iba1 expression) and astrocyte (increased GFAP expression) activation; [b] apoptotic signaling and cell death/neurodegeneration indicated by increased TUNEL and BID positive cell staining , decreased neuronal nuclei (NeuN) staining, and increased protein expression of proapoptotic AIF, BAX, and caspases; [c] decreased synaptic plasticity and function shown by deficits observed in long term potentiation (LTP) in brain slice preparations and decreased synaptic protein expression, such as synaptophysin; [d] blood-brain barrier degradation as evidenced by Evans blue dye or other blood-originating tracers entering into brain tissue following TBI; [e] oxidative stress shown by increased production of antioxidants, ROS, or remnants of oxidation such as malondialdehyde using thiobarbituric acid reactive species (TBARS) assays in brain tissue; and finally [f] glutamate


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regulation dysfunction shown by decreases in glutamate transporters, RNA sequencing data, or increases in free extracellular glutamate. A summary of the many studies demonstrating the effects observed in WD, blast, FPI, and CCI TBI models is shown in Table 4. Work demonstrating glutamate toxicity is lacking across all models and generally relies on indirect indicators of glutamate regulation issues. Although rodent models of TBI are extremely useful, development of standardized models of TBI in larger animals should facilitate transfer to clinical trials.258

Incretin- Based Signaling to Counteract TBI Damage Mechanisms GLP-1 and GIP are gastrointestinal peptide hormones with well-studied functions in glucose-dependent insulin secretion. Gcg has an opposing physiological effect, increasing glucose concentrations in the blood. As members of the glucagon peptide family, GLP-1 and Gcg are derived from the same proglucagon gene, while GIP originates from the GIP gene.335 All three peptides are susceptible to cleavage and neutralization by the enzyme DPP-IV, reducing active endogenous levels of each within minutes after production and release.29,30 Three forms of endogenous GLP-1 have been studied for their insulinotropic effects: the full-length form of GLP-1 (1-37), the truncated form of GLP-1 (737), and the truncated amide form (7-36 amide). Only the truncated forms have been found to stimulate glucosedependent insulin secretion, while the full-length form appears inactive.336 Most of the truncated GLP-1 that is produced undergoes amidation on its c-terminal glycine to form GLP-1 (7-36) amide. The benefit from amidation is unknown; it is thought that the amide form is more stable in the circulation, considering that GLP-1 (7-36) amide constitutes 70% or more of circulating GLP-1.337



Figure 4. Incretin-Based Signaling to Counteract TBI

Figure 4. Incretin based therapies target key cell signaling pathways that counteract TBI secondary phase injury. These include mechanisms to decrease apoptosis, inflammation, and oxidative stress, while also promoting repair. *Only demonstrated through GLP-1R agonism. The receptors for GLP-1, GIP, and Gcg are class B G-protein coupled receptors (GPCRs). Although the receptors for GIP and GLP-1 are predominantly expressed in the pancreatic islet cells21,22 and those of Gcg in the liver,338 all three are present in the CNS.339–341 GLP-1R, GIPR, and GcgR mRNA is chiefly expressed in neurons,342 and differential GLP-1R protein expression has been observed throughout the brain.343,344 Under pathological conditions, such as in PD or TBI, expression of GLP-1R mRNA in affected brain regions and cells types can change drastically.345 Observations in a mouse model of PD demonstrate decreased expression in neurons and twofold increases in microglia.93 Additionally, human PD cases show 10-fold increases in GLP-1R expression in the substantia nigra.93 These receptors have seven alpha-helical transmembrane domains (TMDs), a classic signature of all GPCRs, and an N-terminal extracellular domain (ECD) typical of class B GPCRs. The TMDs bind the N-terminal portion of the truncated GLP-1 peptide and the ECD binds the C-terminal portion of the peptide,346 with multiple binding sites biasing activated intracellular cascades.347–349 Unlike class A GPCRs, the class B ECD acts as more than an affinity trap, as both the


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ECD and TMD are responsible for class B GPCR activation.350 All three receptors’ activation can lead to neuroprotection and neurotrophic effects through multiple pathways.

Activated receptors interact with Gαs and dissociates the trimeric G protein to activate adenylyl cyclase and subsequent conversion of ATP to cAMP27,335,351 (Figure 4). Upon GLP-1 addition, cAMP concentrations reach a peak at the 15 minute time-point in PC12 cells,33,51 neuroblastoma SH-SY5Y cells,352 and rat hippocampal cells,35 leading to cAMPdependent protein kinase A (PKA) and exchange protein activated by cAMP (Epac) activation.353–355 PKA directly activates the cAMP-responsive element binding protein (CREB) by phosphorylating Serine 133 on the protein.356 CREB is a transcription factor with a well-studied role in neuronal plasticity and neuronal survival; it is regulated by multiple pathways in addition to the cAMP associated route, including the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT pathway.357 Epac activation leads to similar downstream events

354.

Increasing circulation times of

endogenous GLP-1, GIP, and Gcg via DPP-IV inhibition increases CREB activation.91 Furthermore, Perry et al.33 showed that activation of PKA non-essentially enhances GLP-1 mediated neuroplasticity in PC12 cells, and PI3K and ERK were found to play a role in neurite extension as a result of GLP-1R activation.33

The mechanism of GLP-1R/GIPR/GcgR activation of the PI3K pathway is unclear. However, GLP-1R appears to initiate this neurotrophic pathway near its beginning, as activation of the upstream protein, insulin receptor substrate-1 (IRS1), was found to be markedly increased one hour after Ex-4 administration in hypothalamic neurons358 (Figure 4). Downstream, the neuronal PI3K pathway branches to produce a variety of protective and neuroplastic effects. AKT, also known as Protein Kinase B (PKB), promotes cell survival by phosphorylating and thereby sequestering proapoptotic protein Bad, which normally heterodimerizes and neutralizes the mitochondria associated antiapoptotic protein, Bcl-2. In addition, AKT inhibits p53359, Forkhead box protein O1/03 (FOXO1/03), and subsequent production of pro-apoptotic proteins 335,360. AKT also promotes the activation of mTOR which supports neuronal differentiation and growth by increasing protein synthesis, pyrimidine synthesis, and preventing autophagy.360 Direct phosphorylation of CREB by AKT further promotes cell survival, possibly in part by inducing the expression of Bcl-2.361 Numerous benefits of activation of CREB and downstream cAMP responsive element (CRE) by a GLP-1/GIP/Gcg receptor triagonist were recently described in a mouse model of AD.79 Furthermore, in a secondary analysis of the recent successful 48-week



Exenatide-PD trial,67 researchers extracted neuronal derived exosomes from blood serum of human participants, and within these exosomes, found increased protein levels of IRS-1, AKT, and mTOR.362 These findings present a clinical context for the positive outcomes of Exenatide-PD trial, which noted improvements in motor scores for patients, and furthers understanding of GLP-1R agonism in the human CNS.

Following TBI, much of the oxidative stress, excitotoxicity and inflammation observed in the injured brain can be attenuated by incretin-based therapies. Such actions are a clear parallel to anti-apoptotic effects provided by GLP-1 and analogues on pancreatic cells21 and have been demonstrated in neuronal cell culture models51 and recent mouse models of stroke and chronic cerebral hypofusion.363,364 Pretreatment of -cells with Ex-4 and subsequent induction of oxidative stress via hydrogen peroxide (H2O2) addition resulted in a 41.7% decrease in apoptosis. This was mediated by AKT inhibition of the c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 3 (GSK3)-mediated apoptosis pathway365 (Figure 4). A GLP-1/GIP/Gcg triagonist was also shown to block activation of GSK3 and is thought to be a potential mechanism for rescue of neuronal plasticity deficits in a mouse model of AD.79 Activation of caspase-9 and -3, two important mediators of apoptosis, was also reduced as a result of this pretreatment. Treatment with Ex-4 in similar H2O2- induced oxidative stress experiments resulted in Epac-dependent increases in -cell production of prominent antioxidant enzymes, including catalase, glutathione peroxidase-1, and manganese superoxide dismutase (MnSOD).353 Following oxidative stress, activation of PKA and induction of oxidative defense genes HO-1 and NQO1 via Ex-4 improved cell viability in human umbilical vein endothelial cells.366 A recent report describes mitigation of oxidative DNA damage in a model of stroke through neuronal GLP-1R activation and subsequent enhancement of PI3K-AKT-induced expression of apurinic/apyrimidinic endonuclease 1 (APE1),367 a protein key to amplifying base excision repair of oxidative DNA damage368,369 (Figure 4). Further evidence for the antioxidant effects of incretin-based therapies comes from the use of the DPP-IV inhibitor sitagliptin in a mouse model of TBI, which resulted in increased MnSOD production and overall improved outcomes91 (Table 1). In a model of stroke, GLP-1 analogues induced similar increases in MnSOD production.363

Another important neuroprotective effect of incretin-based therapies includes a strong anti-inflammatory component, namely the reduction of glial cell activation and related cytokine production. In a model of PD, the GLP-1 analogue


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NYLO1 (Table 2) blocked the formation of A1 astrocytes, indicated by decreased C3 immunoreactivity. Significant reduction in the number of activated microglia and subsequent production and release of Il-1, TNF-, and C1q was also observed.93 In this model, blocking the formation of A1 astrocytes proved to be a major mechanism preventing neuronal loss, attributable to the attenuated microglial activation. Yun et al.93 and Athauda & Foltynie360 point out that reduction in microglial activation or activity by GLP-1R agonists may be the primary mechanism for neuroprotection in models of stroke,53,58,370,371 PD,372 ALS64, and other conditions.49,373 GLP-1R agonism in microglia promotes an M2 phenotype induction

58,374

possibly via alternative CREB mediated pathways

375,

increasing the anti-inflammatory and

reparative functions of these cells. In models of TBI and related in vitro studies, incretin-based therapies have shown efficacy in increasing CREB signaling75,83,84,91 and anti-inflammatory effects, including reduced glial cell activation and cytokine production using independent administration of GIP88 and the GLP-1 analogue PT-30274 (Table 1). PARP-1 is involved in microglial activation221 and its inhibited expression by GLP-1 and analogues, shown in models of stroke and chronic cerebral hypofusion,363,364 may provide an additional anti-inflammatory mechanism for GLP-1 based therapies. Finally, inhibition of NF-B downstream of PI3K and AKT is yet another possible mechanism of GLP-1 agonism for the mitigation of inflammation-related sequalae.360 NF-B inhibition is neuroprotective in models of PD376 and TBI,232 with DPP-IV inhibitors and GLP-1 analogues significantly suppressing the transcription factor and potentially increasing endogenous inhibitors.93,360 Though NF-B induction is neuroprotective when activated in neurons, blockage of glial cell NF-B induction supersedes this potential benefit through mitigation of the release of inflammatory mediators and other neurotoxic proteins.377

In synopsis, incretin-based therapies present a multitude of beneficial signaling endpoints that can readily be applied to TBI pathophysiological sequalae (Table 4). Considering the strong neurotrophic/neuroprotective, anti-oxidant, and anti-inflammatory components that underlie the actions of incretin-based therapies, all of which are beneficial for TBI pathophysiological effects, these compounds appear to be ideally suited for introduction into clinical trials for TBI.

Targeting Specific Intracellular Pathways



As shown above, incretin-based mimetics affect a wide variety of intracellular pathways. Interest in the many signaling profiles of GPCRs is growing, including that of incretin receptors, and investigation of how these diverse pathways are activated is an increasingly important area of research for the development of more effective, disease-specific therapies.378 Evidence of various biased activation sites of incretin receptors, specifically GLP-1R, adds an additional layer of complexity to their known pleiotropic signaling and provides possible opportunities for optimization of signaling pathways to best treat TBI or other neurological disorders with reduced side effects. Recent work has described specific binding sites of the GLP-1R receptor that preferentially activate intracellular calcium recruitment and cAMP and pERK1/2 signaling in insulinoma cells.349 Adding to this knowledge, replacing the α-amino acids of the endogenous GLP-1 backbone with β-amino acids has helped characterize further nuances in these signaling paradigms.379 Biased agonism is not exclusively a function of receptor binding sites and ligand structure, but can also depend on effector molecules and adapter proteins recruited to or allosteric modulation of the GPCR.380 β-arrestin proteins are regulators of GPCR activity, including receptor desensitization.381 Varying the amino acid backbone of GLP-1R agonists differentially promotes characteristic G-protein signaling (cAMP, etc.) and β-arrestin recruitment,382 with the impacts of effector molecules or adapter proteins on downstream signaling and phenotypic responses varying.383 In pancreatic βcells, for example, β-arrestin 1 recruitment has been shown to help facilitate the antiapoptotic effects of GLP-1 through the phosphorylation of the pro-apoptotic protein, Bad.384

As yet, little to no information is available elucidating the occurrence of GLP-1R biased agonism in nervous system tissue or in relation to contributions of GIP or glucagon,383 but this clearly appears to be a potentially fruitful avenue to evaluate. Furthermore, the differential expression patterns of incretin receptors in neurons or microglia also may add another level of intricacy to understanding the diverse pathways initiated by both endogenous and designer agonists. Interest in non-peptide GLP-1R agonists is substantial and an example is the experimental diabetes drug TTP273 (Table 2). TTP273 appears to be a functionally biased ligand with a favorable tolerability and low incidence nausea and vomiting.385 Interestingly, TTP273 lacks any β-arrestin 2 recruitment typical of endogenous GLP-1R agonists,385 which promotes stereotypic GPCR signaling cascades.386 β-arrestin 2 recruitment, however, can attenuate this normal signaling pattern, with the GLP-1R/β-arrestin 2 complex increasing the receptor’s affinity for glucagon and internalization of the receptor

386.

The route of administration (e.g. oral, subcutaneous injection, or transdermal) can


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also impact a drug’s time-dependent pharmacological actions as well as compliance.387 Preliminary evidence shows that TTP273 has differential effects on food intake depending on its route of administration.385 Delivery to target sites is also paramount to initial drug design and, for the treatment of neurological disorders a reasonable BBB penetration is vital to support therapeutic levels being achieved in brain. In the case of TTP273 that was designed for T2DM and likely not intended for neurological disorders, BBB permeability was probably not a key concern during the agent’s initial design, with preliminary evidence showing that brain drug concentrations are only 2 to 3% of plasma’s,388 similar to Ex4.67,74 With these many considerations, understanding the mechanisms of biased agonist signaling may allow for the development of disease tailored drugs, particularly in relation to incretin receptor agonists.

Conclusion In the present review, we have provided an overview of the current literature supporting the use of incretin-based therapies across a wide variety of nervous system disease and injury models, including TBI. The safety, availability, and demonstrated efficacy of incretin-based therapies make them ideal for rapid introduction into clinical trials to evaluate alternative uses to their already prescribed treatment of metabolic diseases. There is great and immediate need for an effective drug therapy for treatment of secondary injury related to TBI, especially considering the long-term consequences of even a single TBI injury, including the development of conditions such as PD and AD that can be triggered by TBI. Considering the dangers of even just one TBI, it is encouraging that the general public is heeding current science and increasingly seeking medical attention for head injuries. Unfortunately, there are no treatments for secondary injuries associated with TBI. Incretin-based therapies can fill this pharmacological void, and there is sound and increasing scientific evidence of using translationally relevant doses across both cellular and animal models of brain injury to support trials of evaluating incretin-based mimetics in human TBI. Biased, designer incretin-receptor agonists are currently in development and further work needs to be done to tailor these compounds to neurological disorders. The next questions to consider are as follows: [a] Which of the available agents should be first appraised?; [b] Which TBI subjects (mild, moderate or severe) should be evaluated in clinical trials?; [c] When should treatment start and how should it be initiated to rapidly achieve and maintain therapeutic brain levels?; [d] How long should treatment continue?; and [e] What biochemical and clinical outcome measures should be evaluated to define target engagement and response? Using the dose and route of administration approved and found effective for the treatment of T2DM, it is encouraging that several FDA approved incretin-based therapies and other emerging analogues are



making their way into clinical trials for neurological diseases. A concerted effort is needed to effectively apply these safe and efficacious drugs to trials for TBI treatment.

Acknowledgements/Disclosure: We would like to thank Lauren Brick of the Visual Media core at the National Institute on Drug Abuse for artistic assistance and design on figures throughout the manuscript. Work described here was funded in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. LO and TK are supported by the Swedish Medical Research Council and Brain Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflicts of Interest: The National Institutes of Health holds issued and in process patents on the use of incretin mimetics for the treatment of neurodegenerative disorders through the work of NHG who has assigned all his rights to the National Institute on Aging. All other coauthors declare no conflicts of interest.

References (1)

Harrison-Felix, C.; Kolakowsky-Hayner, S. A.; Hammond, F. M.; Wang, R.; Englander, J.; DamsOʼConnor, K.; Kreider, S. E. D.; Novack, T. A.; Diaz-Arrastia, R. Mortality After Surviving Traumatic Brain Injury: Risks Based on Age Groups. J. Head Trauma Rehabil. 2012, 27 (6), E45–E56. https://doi.org/10.1097/HTR.0B013E31827340BA.

(2)

Saatman, K. E.; Duhaime, A.-C.; Bullock, R.; Maas, A. I. R.; Valadka, A.; Manley, G. T. Classification of Traumatic Brain Injury for Targeted Therapies. J. Neurotrauma 2008, 25 (7), 719– 738. https://doi.org/10.1089/neu.2008.0586.

(3)

Deselms, H.; Maggio, N.; Rubovitch, V.; Chapman, J.; Schreiber, S.; Tweedie, D.; Kim, D. S.; Greig, N. H.; Pick, C. G. Novel Pharmaceutical Treatments for Minimal Traumatic Brain Injury and Evaluation of Animal Models and Methodologies Supporting Their Development. J. Neurosci.

Methods 2016, 272, 69–76. https://doi.org/10.1016/j.jneumeth.2016.02.002. (4)

Greve, M. W.; Zink, B. J. Pathophysiology of Traumatic Brain Injury. Mt. Sinai J. Med. 2009, 76 (2), 97–104. https://doi.org/10.1093/bja/aem131.


Page 32 of 68

Page 33 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(5)

Pearn, M. L.; Niesman, I. R.; Egawa, J.; Sawada, A.; Almenar-Queralt, A.; Shah, S. B.; Duckworth, J. L.; Head, B. P. Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics. Cellular and Molecular Neurobiology. Springer US May 6, 2017, pp 571–585. https://doi.org/10.1007/s10571-016-0400-1.

(6)

U.S. Food and Drug Administration. Traumatic Brain Injury: FDA Actions and Research https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm519116.htm (accessed Oct 10, 2018).

(7)

Paniak, C.; Reynolds, S.; Phillips, K.; Toller-Lobe, G.; Melnyk, A.; Nagy, J. Patient Complaints within 1 Month of Mild Traumatic Brain Injury: A Controlled Study. Arch. Clin. Neuropsychol. 2002,

17 (4), 319–334. https://doi.org/10.1016/S0887-6177(01)00115-9. (8)

Rabinowitz, A. R.; Levin, H. S. Cognitive Sequelae of Traumatic Brain Injury. Psychiatric Clinics of

North America. NIH Public Access March 2014, pp 1–11. https://doi.org/10.1016/j.psc.2013.11.004. (9)

Gareis, M.; Bauer, J.; Von Montgelas, A.; Gedek, B. Stimulation of Aflatoxin B’1 and T-2 Toxin Production by Sorbic Acid. Appl. Environ. Microbiol. 1984, 47 (2), 416–418. https://doi.org/10.3389/fnhum.2013.00030.

(10)

Daneshvar, D. H.; Riley, D. O.; Nowinski, C. J.; McKee, A. C.; Stern, R. A.; Cantu, R. C. LongTerm Consequences: Effects on Normal Development Profile After Concussion. Physical Medicine

and Rehabilitation Clinics of North America. NIH Public Access November 2011, pp 683–700. https://doi.org/10.1016/j.pmr.2011.08.009. (11)

Gardner, R. C.; Yaffe, K. Epidemiology of Mild Traumatic Brain Injury and Neurodegenerative Disease. Mol. Cell. Neurosci. 2015, 66 (Pt B), 75–80. https://doi.org/10.1016/j.mcn.2015.03.001.

(12)

Kalkonde, Y. V.; Jawaid, A.; Qureshi, S. U.; Shirani, P.; Wheaton, M.; Pinto-Patarroyo, G. P.; Schulz, P. E. Medical and Environmental Risk Factors Associated with Frontotemporal Dementia: A Case-Control Study in a Veteran Population. Alzheimer’s Dement. 2012, 8 (3), 204–210. https://doi.org/10.1016/j.jalz.2011.03.011.

(13)

Masel, B. E.; DeWitt, D. S. Traumatic Brain Injury: A Disease Process, Not an Event. J.

Neurotrauma 2010, 27 (8), 1529–1540. https://doi.org/10.1089/neu.2010.1358. (14)

Greig, N. H.; Tweedie, D.; Rachmany, L.; Li, Y.; Rubovitch, V.; Schreiber, S.; Chiang, Y.-H.; Hoffer, B. J.; Miller, J.; Lahiri, D. K.; et al. Incretin Mimetics as Pharmacologic Tools to Elucidate and as a New Drug Strategy to Treat Traumatic Brain Injury. Alzheimer’s Dement. 2014, 10 (1 Suppl), S62-75. https://doi.org/10.1016/j.jalz.2013.12.011.

(15)

Hoffer, B. J.; Pick, C. G.; Hoffer, M. E.; Becker, R. E.; Chiang, Y. H.; Greig, N. H. Repositioning Drugs for Traumatic Brain Injury - N-Acetyl Cysteine and Phenserine. Journal of Biomedical

Science. BioMed Central September 9, 2017, p 71. https://doi.org/10.1186/s12929-017-0377-1. (16)

Wang, J.-Y.; Huang, Y.-N.; Chiu, C.-C.; Tweedie, D.; Luo, W.; Pick, C. G.; Chou, S.-Y.; Luo, Y.; Hoffer, B. J.; Greig, N. H.; et al. Pomalidomide Mitigates Neuronal Loss, Neuroinflammation, and Behavioral Impairments Induced by Traumatic Brain Injury in Rat. J. Neuroinflammation 2016, 13



(1), 168. https://doi.org/10.1186/s12974-016-0631-6. (17)

Hall, E. D.; Wang, J. A.; Miller, D. M.; Cebak, J. E.; Hill, R. L. Newer Pharmacological Approaches for Antioxidant Neuroprotection in Traumatic Brain Injury. Neuropharmacology 2018. https://doi.org/10.1016/J.NEUROPHARM.2018.08.005.

(18)

Rachmany, L.; Tweedie, D.; Rubovitch, V.; Yu, Q.-S.; Li, Y.; Wang, J.-Y.; Pick, C. G.; Greig, N. H. Cognitive Impairments Accompanying Rodent Mild Traumatic Brain Injury Involve P53-Dependent Neuronal Cell Death and Are Ameliorated by the Tetrahydrobenzothiazole PFT-α. PLoS One 2013, 8 (11), e79837. https://doi.org/10.1371/journal.pone.0079837.

(19)

Tweedie, D.; Fukui, K.; Li, Y.; Yu, Q. S.; Barak, S.; Tamargo, I. A.; Rubovitch, V.; Holloway, H. W.; Lehrmann, E.; Wood, W. H.; et al. Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms. PLoS One 2016, 11 (6), e0156493. https://doi.org/10.1371/journal.pone.0156493.

(20)

Huang, Y.-N.; Yang, L.-Y.; Greig, N. H.; Wang, Y.-C.; Lai, C.-C.; Wang, J.-Y. Neuroprotective Effects of Pifithrin-α against Traumatic Brain Injury in the Striatum through Suppression of Neuroinflammation, Oxidative Stress, Autophagy, and Apoptosis. Sci. Rep. 2018, 8 (1), 2368. https://doi.org/10.1038/s41598-018-19654-x.

(21)

Campbell, J. E.; Drucker, D. J. J. Pharmacology, Physiology, and Mechanisms of Incretin Hormone Action. Cell Metab. 2013, 17 (6), 819–837. https://doi.org/10.1016/j.cmet.2013.04.008.

(22)

Lovshin, J. A.; Drucker, D. J. Incretin-Based Therapies for Type 2 Diabetes Mellitus. Nat. Rev.

Endocrinol. 2009, 5 (5), 262–269. https://doi.org/10.1038/nrendo.2009.48. (23)

Drucker, D. J.; Buse, J. B.; Taylor, K.; Kendall, D. M.; Trautmann, M.; Zhuang, D.; Porter, L. Exenatide Once Weekly versus Twice Daily for the Treatment of Type 2 Diabetes: A Randomised, Open-Label, Non-Inferiority Study. Lancet 2008, 372 (9645), 1240–1250. https://doi.org/10.1016/S0140-6736(08)61206-4.

(24)

Nauck, M.; Stöckmann, F.; Ebert, R.; Creutzfeldt, W. Reduced Incretin Effect in Type 2 (NonInsulin-Dependent) Diabetes. Diabetologia 1986, 29 (1), 46–52. https://doi.org/https://doi.org/10.1007/BF02427280.

(25)

Capozzi, M. E.; DiMarchi, R. D.; Tschöp, M. H.; Finan, B.; Campbell, J. E. Targeting the Incretin/Glucagon System With Triagonists to Treat Diabetes. Endocr. Rev. 2018, 39 (5), 719–738. https://doi.org/10.1210/er.2018-00117.

(26)

Vollmer, K.; Hoist, J. J.; Bailer, B.; Ellrlchmann, M.; Nauck, M. A.; Schmidt, W. E.; Meier, J. J. Predictors of Incretin Concentrations in Subjects with Normal, Impaired, and Diabetic Glucose Tolerance. Diabetes 2008, 57 (3), 678–687. https://doi.org/10.2337/db07-1124.

(27)

Müller, T. D.; Finan, B.; Clemmensen, C.; DiMarchi, R. D.; Tschöp, M. H. The New Biology and Pharmacology of Glucagon. Physiol. Rev. 2017, 97 (2), 721–766. https://doi.org/10.1152/physrev.00025.2016.


Page 34 of 68

Page 35 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(28)

Tschöp, M. H.; Finan, B.; Clemmensen, C.; Gelfanov, V.; Perez-Tilve, D.; Müller, T. D.; DiMarchi, R. D. Unimolecular Polypharmacy for Treatment of Diabetes and Obesity. Cell Metab. 2016, 24 (1), 51–62. https://doi.org/10.1016/j.cmet.2016.06.021.

(29)

Deacon, C. F. Circulation and Degradation of GIP and GLP-1. Hormone and Metabolic Research. © Georg Thieme Verlag KG Stuttgart · New York November 18, 2004, pp 761–765. https://doi.org/10.1055/s-2004-826160.

(30)

Pospisilik, J. A.; Hinke, S. A.; Pederson, R. A.; Hoffmann, T.; Rosche, F.; Schlenzig, D.; Glund, K.; Heiser, U.; Mcintosh, C. H. S.; Demuth, H.-U. Metabolism of Glucagon by Dipeptidyl Peptidase IV (CD26). Regul. Pept. 2001, 96, 133–141. https://doi.org/https://doi.org/10.1016/S01670115(00)00170-1.

(31)

Brandt, S. J.; Götz, A.; Tschöp, M. H.; Müller, T. D. Gut Hormone Polyagonists for the Treatment of Type 2 Diabetes. Peptides 2018, 100, 190–201. https://doi.org/10.1016/j.peptides.2017.12.021.

(32)

Eng, J.; Kleinman, W. A.; Singh, L.; Singh, G.; Raufman, J. P. Isolation and Characterization of Exendin-4, an Exendin-3 Analogue, from Heloderma Suspectum Venom: Further Evidence for an Exendin Receptor on Dispersed Acini from Guinea Pig Pancreas. J. Biol. Chem. 1992, 267 (11), 7402–7405. https://doi.org/10.1007/s10529-011-0745-y.

(33)

Perry, T.; Lahiri, D. K.; Chen, D.; Zhou, J.; Shaw, K. T. Y.; Egan, J. M.; Greig, N. H. A Novel Neurotrophic Property of Glucagon-like Peptide 1: A Promoter of Nerve Growth Factor-Mediated Differentiation in PC12 Cells. J. Pharmacol. Exp. Ther. 2002, 300 (3), 958–966. https://doi.org/https://doi.org/10.1124/jpet.300.3.958.

(34)

Perry, T.; Lahiri, D. K.; Sambamurti, K.; Chen, D.; Mattson, M. P.; Egan, J. M.; Greig, N. H. Glucagon-like Peptide-1 Decreases Endogenous Amyloid-Beta Peptide (Abeta) Levels and Protects Hippocampal Neurons from Death Induced by Abeta and Iron. J. Neurosci. Res. 2003, 72 (5), 603–612. https://doi.org/10.1002/jnr.10611.

(35)

Perry, T. Protection and Reversal of Excitotoxic Neuronal Damage by Glucagon-Like Peptide-1 and Exendin-4. J. Pharmacol. Exp. Ther. 2002, 302 (3), 881–888. https://doi.org/10.1124/jpet.102.037481.

(36)

Salcedo, I.; Tweedie, D.; Li, Y.; Greig, N. H. Neuroprotective and Neurotrophic Actions of Glucagon-like Peptide-1: An Emerging Opportunity to Treat Neurodegenerative and Cerebrovascular Disorders. British Journal of Pharmacology. Wiley-Blackwell July 2012, pp 1586– 1599. https://doi.org/10.1111/j.1476-5381.2012.01971.x.

(37)

Kim, D. S.; Choi, H.-I.; Wang, Y.; Luo, Y.; Hoffer, B. J.; Greig, N. H. A New Treatment Strategy for Parkinson’s Disease through the Gut-Brain Axis: The Glucagon-Like Peptide-1 Receptor Pathway.

Cell Transplant. 2017, 26 (9), 1560–1571. https://doi.org/10.1177/0963689717721234. (38)

Frias, J. P.; Nauck, M. A.; Van, J.; Kutner, M. E.; Cui, X.; Benson, C.; Urva, S.; Gimeno, R. E.; Milicevic, Z.; Robins, D.; et al. Efficacy and Safety of LY3298176, a Novel Dual GIP and GLP-1 Receptor Agonist, in Patients with Type 2 Diabetes: A Randomised, Placebo-Controlled and



Active Comparator-Controlled Phase 2 Trial. Lancet 2018. https://doi.org/10.1016/S01406736(18)32260-8. (39)

Jalewa, J.; Sharma, M. K.; Gengler, S.; Hölscher, C. A Novel GLP-1/GIP Dual Receptor Agonist Protects from 6-OHDA Lesion in a Rat Model of Parkinson’s Disease. Neuropharmacology 2017,

117, 238–248. https://doi.org/10.1016/j.neuropharm.2017.02.013. (40)

Ji, C.; Xue, G.-F.; Lijun, C.; Feng, P.; Li, D.; Li, L.; Li, G.; Hölscher, C. A Novel Dual GLP-1 and GIP Receptor Agonist Is Neuroprotective in the MPTP Mouse Model of Parkinson′s Disease by Increasing Expression of BNDF. Brain Res. 2016, 1634, 1–11. https://doi.org/10.1016/J.BRAINRES.2015.09.035.

(41)

Finan, B.; Ma, T.; Ottaway, N.; Müller, T. D.; Habegger, K. M.; Heppner, K. M.; Kirchner, H.; Holland, J.; Hembree, J.; Raver, C.; et al. Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans. Sci. Transl. Med. 2013, 5 (209). https://doi.org/10.1126/scitranslmed.3007218.

(42)

Finan, B.; Yang, B.; Ottaway, N.; Smiley, D. L.; Ma, T.; Clemmensen, C.; Chabenne, J.; Zhang, L.; Habegger, K. M.; Fischer, K.; et al. A Rationally Designed Monomeric Peptide Triagonist Corrects Obesity and Diabetes in Rodents. Nat. Med. 2015, 21 (1), 27–36. https://doi.org/10.1038/nm.3761.

(43)

Kim, J. A.; Lee, S.; Lee, S. H.; Jung, S. Y.; Kim, Y. H.; Choi, I. Y.; Kim, S. J. Neuroprotective Effects of HM15211, a Novel Long-Acting GLP-1/GIP/Glucagon Triple Agonist in the Neurodegenerative Disease Models. Diabetes 2018, 67 (Supplement 1), 1107–P. https://doi.org/10.2337/db18-1107-P.

(44)

Sloop, K. W.; Briere, D. A.; Emmerson, P. J.; Willard, F. S. Beyond Glucagon-like Peptide-1: Is GProtein Coupled Receptor Polypharmacology the Path Forward to Treating Metabolic Diseases?

ACS Pharmacol. Transl. Sci. 2018, 1 (1), 3–11. https://doi.org/10.1021/acsptsci.8b00009. (45)

Trujillo, J. M.; Nuffer, W.; Ellis, S. L. GLP-1 Receptor Agonists: A Review of Head-to-Head Clinical Studies. Therapeutic Advances in Endocrinology and Metabolism. SAGE Publications February 2015, pp 19–28. https://doi.org/10.1177/2042018814559725.

(46)

Ali, S.; Lamont, B. J.; Charron, M. J.; Drucker, D. J. Dual Elimination of the Glucagon and GLP-1 Receptors in Mice Reveals Plasticity in the Incretin Axis. J. Clin. Invest. 2011, 121 (5), 1917–1929. https://doi.org/10.1172/JCI43615.

(47)

Lee, C.-H.; Jeon, S. J.; Cho, K. S.; Moon, E.; Sapkota, A.; Jun, H. S.; Ryu, J. H.; Choi, J. W. Activation of Glucagon-Like Peptide-1 Receptor Promotes Neuroprotection in Experimental Autoimmune Encephalomyelitis by Reducing Neuroinflammatory Responses. Mol. Neurobiol. 2018, 55 (4), 3007–3020. https://doi.org/10.1007/s12035-017-0550-2.

(48)

Hernández, C.; Bogdanov, P.; Solà-Adell, C.; Sampedro, J.; Valeri, M.; Genís, X.; Simó-Servat, O.; García-Ramírez, M.; Simó, R. Topical Administration of DPP-IV Inhibitors Prevents Retinal Neurodegeneration in Experimental Diabetes. Diabetologia 2017, 60 (11), 2285–2298. https://doi.org/10.1007/s00125-017-4388-y.


Page 36 of 68

Page 37 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(49)

Gonçalves, A.; Lin, C.-M.; Muthusamy, A.; Fontes-Ribeiro, C.; Ambrósio, A. F.; Abcouwer, S. F.; Fernandes, R.; Antonetti, D. A. Protective Effect of a GLP-1 Analog on Ischemia-Reperfusion Induced Blood-Retinal Barrier Breakdown and Inflammation. Investig. Opthalmology Vis. Sci. 2016, 57 (6), 2584–2592. https://doi.org/10.1167/iovs.15-19006.

(50)

Marlet, I. R.; Ölmestig, J. N. E.; Vilsbøll, T.; Rungby, J.; Kruuse, C. Neuroprotective Mechanisms of Glucagon-like Peptide-1-Based Therapies in Ischaemic Stroke: A Systematic Review Based on Pre-Clinical Studies. Basic and Clinical Pharmacology and Toxicology. Wiley/Blackwell (10.1111) June 1, 2018, pp 559–569. https://doi.org/10.1111/bcpt.12974.

(51)

Li, Y.; Perry, T.; Kindy, M. S.; Harvey, B. K.; Tweedie, D.; Holloway, H. W.; Powers, K.; Shen, H.; Egan, J. M.; Sambamurti, K.; et al. GLP-1 Receptor Stimulation Preserves Primary Cortical and Dopaminergic Neurons in Cellular and Rodent Models of Stroke and Parkinsonism. Proc. Natl.

Acad. Sci. 2009, 106 (4), 1285–1290. https://doi.org/10.1073/pnas.0806720106. (52)

Zhang, H.; Liu, Y.; Guan, S.; Qu, D.; Wang, L.; Wang, X.; Li, X.; Zhou, S.; Zhou, Y.; Wang, N.; et al. An Orally Active Allosteric GLP-1 Receptor Agonist Is Neuroprotective in Cellular and Rodent Models of Stroke. PLoS One 2016, 11 (2), e0148827. https://doi.org/10.1371/journal.pone.0148827.

(53)

Teramoto, S.; Miyamoto, N.; Yatomi, K.; Tanaka, Y.; Oishi, H.; Arai, H.; Hattori, N.; Urabe, T. Exendin-4, a Glucagon-like Peptide-1 Receptor Agonist, Provides Neuroprotection in Mice Transient Focal Cerebral Ischemia. J. Cereb. Blood Flow Metab. 2011, 31 (8), 1696–1705. https://doi.org/10.1038/jcbfm.2011.51.

(54)

Hölscher, C. Novel Dual GLP-1/GIP Receptor Agonists Show Neuroprotective Effects in Alzheimer’s and Parkinson’s Disease Models. Neuropharmacology 2018, 136 (Pt B), 251–259. https://doi.org/10.1016/j.neuropharm.2018.01.040.

(55)

Cao, Y.; Hölscher, C.; Hu, M. M.; Wang, T.; Zhao, F.; Bai, Y.; Zhang, J.; Wu, M. N.; Qi, J. S. DA5CH, a Novel GLP-1/GIP Dual Agonist, Effectively Ameliorates the Cognitive Impairments and Pathology in the APP/PS1 Mouse Model of Alzheimer’s Disease. Eur. J. Pharmacol. 2018, 827, 215–226. https://doi.org/10.1016/j.ejphar.2018.03.024.

(56)

Li, Y.; Duffy, K. B.; Ottinger, M. A.; Ray, B.; Bailey, J. A.; Holloway, H. W.; Tweedie, D.; Perry, T.; Mattson, M. P.; Kapogiannis, D.; et al. GLP-1 Receptor Stimulation Reduces Amyloid-β Peptide Accumulation and Cytotoxicity in Cellular and Animal Models of Alzheimer’s Disease. J.

Alzheimer’s Dis. 2010, 19 (4), 1205–1219. https://doi.org/10.3233/JAD-2010-1314. (57)

McClean, P. L.; Parthsarathy, V.; Faivre, E.; Holscher, C. The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer’s Disease. J. Neurosci. 2011, 31 (17), 6587–6594. https://doi.org/10.1523/JNEUROSCI.0529-11.2011.

(58)

Darsalia, V.; Hua, S.; Larsson, M.; Mallard, C.; Nathanson, D.; Nyström, T.; Sjöholm, Å.; Johansson, M. E.; Patrone, C. Exendin-4 Reduces Ischemic Brain Injury in Normal and Aged Type 2 Diabetic Mice and Promotes Microglial M2 Polarization. PLoS One 2014, 9 (8), e103114.



https://doi.org/10.1371/journal.pone.0103114. (59)

Liu, W.; Jalewa, J.; Sharma, M.; Li, G.; Li, L.; Hölscher, C. Neuroprotective Effects of Lixisenatide and Liraglutide in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson’s Disease. Neuroscience 2015, 303, 42–50. https://doi.org/10.1016/j.neuroscience.2015.06.054.

(60)

Sancandi, M.; Schul, E. V.; Economides, G.; CONSTANTI, A.; Mercer, A. Structural Changes Observed in the Piriform Cortex in a Rat Model of Pre-Motor Parkinson’s Disease. Front. Cell.

Neurosci. 2018, 12, 479. https://doi.org/10.3389/FNCEL.2018.00479. (61)

Cao, L.; Li, D.; Feng, P.; Li, L.; Xue, G.-F.; Li, G.; Hölscher, C. A Novel Dual GLP-1 and GIP Incretin Receptor Agonist Is Neuroprotective in a Mouse Model of Parkinson’s Disease by Reducing Chronic Inflammation in the Brain. Neuroreport 2016, 27 (6), 384–391. https://doi.org/10.1097/WNR.0000000000000548.

(62)

Harkavyi, A.; Rampersaud, N.; Whitton, P. S. Neuroprotection by Exendin-4 Is GLP-1 Receptor Specific but DA D 3 Receptor Dependent, Causing Altered BrdU Incorporation in Subventricular Zone and Substantia Nigra. J. Neurodegener. Dis. 2013, 2013, 1–9. https://doi.org/10.1155/2013/407152.

(63)

Zhang, Y. F.; Chen, Y. M.; Li, L.; Hölscher, C. Neuroprotective Effects of (Val8)GLP-1-Glu-PAL in the MPTP Parkinson’s Disease Mouse Model. Behav. Brain Res. 2015, 293, 107–113. https://doi.org/10.1016/j.bbr.2015.07.021.

(64)

Li, Y.; Chigurupati, S.; Holloway, H. W.; Mughal, M.; Tweedie, D.; Bruestle, D. A.; Mattson, M. P.; Wang, Y.; Harvey, B. K.; Ray, B.; et al. Exendin-4 Ameliorates Motor Neuron Degeneration in Cellular and Animal Models of Amyotrophic Lateral Sclerosis. PLoS One 2012, 7 (2), e32008. https://doi.org/10.1371/journal.pone.0032008.

(65)

Bramlett, H. M.; Dietrich, W. D. Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes. J. Neurotrauma 2015, 32 (23), 1834–1848. https://doi.org/10.1089/neu.2014.3352.

(66)

Becker, R. E.; Kapogiannis, D.; Greig, N. H. Does Traumatic Brain Injury Hold the Key to the Alzheimer’s Disease Puzzle? Alzheimer’s Dement. 2018, 14 (4), 431–443. https://doi.org/10.1016/j.jalz.2017.11.007.

(67)

Athauda, D.; Maclagan, K.; Skene, S. S.; Bajwa-Joseph, M.; Letchford, D.; Chowdhury, K.; Hibbert, S.; Budnik, N.; Zampedri, L.; Dickson, J.; et al. Exenatide Once Weekly versus Placebo in Parkinson’s Disease: A Randomised, Double-Blind, Placebo-Controlled Trial. Lancet 2017, 390 (10103), 1664–1675. https://doi.org/10.1016/S0140-6736(17)31585-4.

(68)

Athauda, D.; MacLagan, K.; Budnik, N.; Zampedri, L.; Hibbert, S.; Skene, S. S.; Chowdhury, K.; Aviles-Olmos, I.; Limousin, P.; Foltynie, T. What Effects Might Exenatide Have on Non-Motor Symptoms in Parkinson’s Disease: A Post Hoc Analysis. J. Parkinsons. Dis. 2018, 8 (2), 247–258. https://doi.org/10.3233/JPD-181329.

(69)

Aviles-Olmos, I.; Dickson, J.; Kefalopoulou, Z.; Djamshidian, A.; Kahan, J.; Ell, P.; Whitton, P.;


Page 38 of 68

Page 39 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Wyse, R.; Isaacs, T.; Lees, A.; et al. Motor and Cognitive Advantages Persist 12 Months After Exenatide Exposure in Parkinson’s Disease. J. Parkinsons. Dis. 2014, 4 (3), 337–344. https://doi.org/10.3233/JPD-140364. (70)

Aviles-Olmos, I.; Dickson, J.; Kefalopoulou, Z.; Djamshidian, A.; Ell, P.; Soderlund, T.; Whitton, P.; Wyse, R.; Isaacs, T.; Lees, A.; et al. Exenatide and the Treatment of Patients with Parkinson’s Disease. J. Clin. Invest. 2013, 123 (6), 2730–2736. https://doi.org/10.1172/JCI68295.

(71)

Gejl, M.; Gjedde, A.; Egefjord, L.; Møller, A.; Hansen, S. B.; Vang, K.; Rodell, A.; Brændgaard, H.; Gottrup, H.; Schacht, A.; et al. In Alzheimer’s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front. Aging Neurosci. 2016, 8 (MAY), 108. https://doi.org/10.3389/fnagi.2016.00108.

(72)

Chen, S.; Yu, S.-J.; Li, Y.; Lecca, D.; Glotfelty, E.; Kim, H. K.; Choi, H.-I.; Hoffer, B. J.; Greig, N. H.; Kim, D.-S.; et al. Post-Treatment with PT302, a Long-Acting Exendin-4 Sustained Release Formulation, Reduces Dopaminergic Neurodegeneration in a 6-Hydroxydopamine Rat Model of Parkinson’s Disease. Sci. Rep. 2018, 8 (1), 10722. https://doi.org/10.1038/s41598-018-28449-z.

(73)

Zhang, L.; Zhang, L.; Li, L.; Hölscher, C. Neuroprotective Effects of the Novel GLP-1 Long Acting Analogue Semaglutide in the MPTP Parkinson’s Disease Mouse Model. Neuropeptides 2018, 71, 70–80. https://doi.org/10.1016/j.npep.2018.07.003.

(74)

Bader, M.; Li, Y.; Lecca, D.; Rubovitch, V.; Tweedie, D.; Glotfelty, E.; Rachmany, L.; Kim, H. K.; Choi, H.-I.; Hoffer, B. J.; et al. Pharmacokinetics and Efficacy of PT302, a Sustained-Release Exenatide Formulation, in a Murine Model of Mild Traumatic Brain Injury. Neurobiol. Dis. 2018,

124, 439–453. https://doi.org/10.1016/j.nbd.2018.11.023. (75)

Tamargo, I. A.; Bader, M.; Li, Y.; Yu, S.-J.; Wang, Y.; Talbot, K.; DiMarchi, R. D.; Pick, C. G.; Greig, N. H. Novel GLP-1R/GIPR Co-Agonist “Twincretin” Is Neuroprotective in Cell and Rodent Models of Mild Traumatic Brain Injury. Exp. Neurol. 2017, 288, 176–186. https://doi.org/10.1016/j.expneurol.2016.11.005.

(76)

Kosaraju, J.; Tam, K. Y.; Basavan, D. Novel Dual GLP-1 and GIP Receptor Analog Attenuates High-Fat Diet-Induced Disease Progression in 3XTg-AD Mice. Alzheimer’s Dement. 2017, 13 (7), P671. https://doi.org/10.1016/j.jalz.2017.06.818.

(77)

Feng, P.; Zhang, X.; Li, D.; Ji, C.; Yuan, Z.; Wang, R.; Xue, G.; Li, G.; Hölscher, C. Two Novel Dual GLP-1/GIP Receptor Agonists Are Neuroprotective in the MPTP Mouse Model of Parkinson’s Disease. Neuropharmacology 2018, 133, 385–394. https://doi.org/10.1016/j.neuropharm.2018.02.012.

(78)

Tai, J.; Liu, W.; Li, Y.; Li, L.; Hölscher, C. Neuroprotective Effects of a Triple GLP-1/GIP/Glucagon Receptor Agonist in the APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease. Brain Res. 2018, 1678, 64–74. https://doi.org/10.1016/j.brainres.2017.10.012.

(79)

Li, T.; Jiao, J. J.; Hölscher, C.; Wu, M. N.; Zhang, J.; Tong, J. Q.; Dong, X. F.; Qu, X. S.; Cao, Y.;



Cai, H. Y.; et al. A Novel GLP-1/GIP/Gcg Triagonist Reduces Cognitive Deficits and Pathology in the 3xTg Mouse Model of Alzheimer’s Disease. Hippocampus 2018, 28 (5), 358–372. https://doi.org/10.1002/hipo.22837. (80)

Heile, A. M. B.; Wallrapp, C.; Klinge, P. M.; Samii, A.; Kassem, M.; Silverberg, G.; Brinker, T. Cerebral Transplantation of Encapsulated Mesenchymal Stem Cells Improves Cellular Pathology after Experimental Traumatic Brain Injury. Neurosci. Lett. 2009, 463 (3), 176–181. https://doi.org/10.1016/j.neulet.2009.07.071.

(81)

Rachmany, L.; Tweedie, D.; Li, Y.; Rubovitch, V.; Holloway, H. W.; Miller, J.; Hoffer, B. J.; Greig, N. H.; Pick, C. G. Exendin-4 Induced Glucagon-like Peptide-1 Receptor Activation Reverses Behavioral Impairments of Mild Traumatic Brain Injury in Mice. Age (Omaha). 2013, 35 (5), 1621– 1636. https://doi.org/10.1007/s11357-012-9464-0.

(82)

Eakin, K.; Li, Y.; Chiang, Y. H.; Hoffer, B. J.; Rosenheim, H.; Greig, N. H.; Miller, J. P. Exendin-4 Ameliorates Traumatic Brain Injury-Induced Cognitive Impairment in Rats. PLoS One 2013, 8 (12), e82016. https://doi.org/10.1371/journal.pone.0082016.

(83)

DellaValle, B.; Hempel, C.; Johansen, F. F.; Kurtzhals, J. A. L. GLP-1 Improves Neuropathology after Murine Cold Lesion Brain Trauma. Ann. Clin. Transl. Neurol. 2014, 1 (9), 721–732. https://doi.org/10.1002/acn3.99.

(84)

Li, Y.; Bader, M.; Tamargo, I.; Rubovitch, V.; Tweedie, D.; Pick, C. G.; Greig, N. H. Liraglutide Is Neurotrophic and Neuroprotective in Neuronal Cultures and Mitigates Mild Traumatic Brain Injury in Mice. J. Neurochem. 2015, 135 (6), 1203–1217. https://doi.org/10.1111/jnc.13169.

(85)

Hakon, J.; Ruscher, K.; Romner, B.; Tomasevic, G. Preservation of the Blood Brain Barrier and Cortical Neuronal Tissue by Liraglutide, a Long Acting Glucagon-like-1 Analogue, after Experimental Traumatic Brain Injury. PLoS One 2015, 10 (3), e0120074. https://doi.org/10.1371/journal.pone.0120074.

(86)

Tweedie, D.; Rachmany, L.; Rubovitch, V.; Li, Y.; Holloway, H. W.; Lehrmann, E.; Zhang, Y.; Becker, K. G.; Perez, E.; Hoffer, B. J.; et al. Blast Traumatic Brain Injury-Induced Cognitive Deficits Are Attenuated by Preinjury or Postinjury Treatment with the Glucagon-like Peptide-1 Receptor Agonist, Exendin-4. Alzheimer’s Dement. 2016, 12 (1), 34–48. https://doi.org/10.1016/j.jalz.2015.07.489.

(87)

Rachmany, L.; Tweedie, D.; Rubovitch, V.; Li, Y.; Holloway, H. W.; Kim, D. S.; Ratliff, W. A.; Saykally, J. N.; Citron, B. A.; Hoffer, B. J.; et al. Exendin-4 Attenuates Blast Traumatic Brain Injury Induced Cognitive Impairments, Losses of Synaptophysin and in Vitro TBI-Induced Hippocampal Cellular Degeneration. Sci. Rep. 2017, 7 (1), 3735. https://doi.org/10.1038/s41598-017-03792-9.

(88)

Yu, Y.-W.; Hsieh, T.-H.; Chen, K.-Y.; Wu, J. C.-C.; Hoffer, B. J.; Greig, N. H.; Li, Y.; Lai, J.-H.; Chang, C.-F.; Lin, J.-W.; et al. Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats. J. Neurotrauma 2016, 33 (22), 2044–2054. https://doi.org/10.1089/neu.2015.4229.


Page 40 of 68

Page 41 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(89)

Fanne, R. A.; Nassar, T.; Heyman, S. N.; Hijazi, N.; Higazi, A. A.-R. Insulin and Glucagon Share the Same Mechanism of Neuroprotection in Diabetic Rats: Role of Glutamate. AJP Regul. Integr.

Comp. Physiol. 2011, 301 (3), R668–R673. https://doi.org/10.1152/ajpregu.00058.2011. (90)

Armstead, W. M.; Kiessling, J. W.; Cines, D. B.; Higazi, A. A.-R. Glucagon Protects Against Impaired NMDA-Mediated Cerebrovasodilation and Cerebral Autoregulation during Hypotension after Brain Injury by Activating CAMP Protein Kinase A and Inhibiting Upregulation of TPA. J.

Neurotrauma 2011, 28 (3), 451–457. https://doi.org/10.1089/neu.2010.1659. (91)

DellaValle, B.; Brix, G. S.; Brock, B.; Gejl, M.; Rungby, J.; Larsen, A. Oral Administration of Sitagliptin Activates CREB and Is Neuroprotective in Murine Model of Brain Trauma. Front.

Pharmacol. 2016, 7, 450. https://doi.org/10.3389/fphar.2016.00450. (92)

Wiberg, S.; Hassager, C.; Schmidt, H.; Thomsen, J. H.; Frydland, M.; Lindholm, M. G.; Høfsten, D. E.; Engstrøm, T.; Køber, L.; Møller, J. E.; et al. Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide after Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial.

Circulation 2016, 134 (25), 2115–2124. https://doi.org/10.1161/CIRCULATIONAHA.116.024088. (93)

Yun, S. P.; Kam, T. I.; Panicker, N.; Kim, S.; Oh, Y.; Park, J. S.; Kwon, S. H.; Park, Y. J.; Karuppagounder, S. S.; Park, H.; et al. Block of A1 Astrocyte Conversion by Microglia Is Neuroprotective in Models of Parkinson’s Disease. Nat. Med. 2018, 24 (7), 931–938. https://doi.org/10.1038/s41591-018-0051-5.

(94)

Nørregaard, P. K.; Deryabina, M. A.; Tofteng Shelton, P.; Fog, J. U.; Daugaard, J. R.; Eriksson, P. O.; Larsen, L. F.; Jessen, L. A Novel GIP Analogue, ZP4165, Enhances Glucagon-like Peptide-1Induced Body Weight Loss and Improves Glycaemic Control in Rodents. Diabetes, Obes. Metab. 2018, 20 (1), 60–68. https://doi.org/10.1111/dom.13034.

(95)

Ambery, P.; Parker, V. E.; Stumvoll, M.; Posch, M. G.; Heise, T.; Plum-Moerschel, L.; Tsai, L. F.; Robertson, D.; Jain, M.; Petrone, M.; et al. MEDI0382, a GLP-1 and Glucagon Receptor Dual Agonist, in Obese or Overweight Patients with Type 2 Diabetes: A Randomised, Controlled, Double-Blind, Ascending Dose and Phase 2a Study. Lancet 2018, 391 (10140), 2607–2618. https://doi.org/10.1016/S0140-6736(18)30726-8.

(96)

Goebel, B.; Schiavon, M.; Visentin, R.; Riz, M.; Man, C. D.; Cobelli, C.; Klabunde, T. Effects of the Novel Dual GLP-1R/GCGR Agonist SAR425899 on Postprandial Glucose Metabolism in Overweight/Obese Subjects with Type 2 Diabetes. Diabetes 2018, 67, 72–OR. https://doi.org/10.2337/db18-72-OR.

(97)

Frias, J. P.; Bastyr, E. J.; Vignati, L.; Tschöp, M. H.; Schmitt, C.; Owen, K.; Christensen, R. H.; DiMarchi, R. D. The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes. Cell Metab. 2017, 26 (2), 343–352.e2. https://doi.org/10.1016/j.cmet.2017.07.011.

(98)

Goldenberg, R.; Gantz, I.; Andryuk, P. J.; O’Neill, E. A.; Kaufman, K. D.; Lai, E.; Wang, Y. N.; Suryawanshi, S.; Engel, S. S. Randomized Clinical Trial Comparing the Efficacy and Safety of



Treatment with the Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor Omarigliptin or the Once-Daily DPP-4 Inhibitor Sitagliptin in Patients with Type 2 Diabetes Inadequately Controlled on M. Diabetes, Obes. Metab. 2017, 19 (3), 394–400. https://doi.org/10.1111/dom.12832. (99)

Ayoub, B. M.; Mowaka, S.; Safar, M. M.; Ashoush, N.; Arafa, M. G.; Michel, H. E.; Tadros, M. M.; Elmazar, M. M.; Mousa, S. A. Repositioning of Omarigliptin as a Once-Weekly Intranasal AntiParkinsonian Agent. Sci. Rep. 2018, 8 (1), 8959. https://doi.org/10.1038/s41598-018-27395-0.

(100) Kim, S. H.; Yoo, J. H.; Lee, W. J.; Park, C. Y. Gemigliptin: An Update of Its Clinical Use in the Management of Type 2 Diabetes Mellitus. Diabetes Metab. J. 2016, 40 (5), 339–353. https://doi.org/10.4093/dmj.2016.40.5.339. (101) Mathieu, C.; Degrande, E. Vildagliptin: A New Oral Treatment for Type 2 Diabetes Mellitus.

Vascular Health and Risk Management. Dove Press 2008, pp 1349–1360. (102) Kishimoto, M. Teneligliptin: A DPP-4 Inhibitor for the Treatment of Type 2 Diabetes. Diabetes.

Metab. Syndr. Obes. 2013, 6, 187–195. https://doi.org/10.2147/DMSO.S35682. (103) Nishio, S.; Abe, M.; Ito, H. Anagliptin in the Treatment of Type 2 Diabetes: Safety, Efficacy, and Patient Acceptability. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. Dove Press 2015, pp 163–171. https://doi.org/10.2147/DMSO.S54679. (104) Taylor, C. A.; Bell, J. M.; Breiding, M. J.; Xu, L. Traumatic Brain Injury–Related Emergency Department Visits, Hospitalizations, and Deaths — United States, 2007 and 2013. MMWR.

Surveill. Summ. 2017, 66 (9), 1–16. https://doi.org/10.15585/mmwr.ss6609a1. (105) Faul, M.; Xu, L.; Wald, M. M.; Coronado, V. G. Traumatic Brain Injury in the United States:

Emergency Department Visits, Hospitalizations and Deaths, 2002-2006; Atlanta, GA, 2010. (106) Marin, J. R.; Weaver, M. D.; Yealy, D. M.; Mannix, R. C. Trends in Visits for Traumatic Brain Injury to Emergency Departments in the United States. JAMA 2014, 311 (18), 1917. https://doi.org/10.1001/jama.2014.3979. (107) Frieden, T. R.; Houry, D.; Baldwin, G. Report to Congress on Traumatic Brain Injury in the United

States: Epidemiology and Rehabilitation; Atlanta, GA, 2015. (108) Haring, R. S.; Canner, J. K.; Asemota, A. O.; George, B. P.; Selvarajah, S.; Haider, A. H.; Schneider, E. B. Trends in Incidence and Severity of Sports-Related Traumatic Brain Injury (TBI) in the Emergency Department, 2006-2011. Brain Inj. 2015, 29 (7–8), 989–992. https://doi.org/10.3109/02699052.2015.1033014. (109) Zaloshnja, E.; Miller, T.; Langlois, J. A.; Selassie, A. W. Prevalence of Long-Term Disability from Traumatic Brain Injury in the Civilian Population of the United States, 2005. J. Head Trauma

Rehabil. 2008, 23 (6), 394–400. https://doi.org/10.1097/01.HTR.0000341435.52004.ac. (110) Langlois, J. A.; Rutland-Brown, W.; Wald, M. M. The Epidemiology and Impact of Traumatic Brain Injury. J Head Trauma Rehabil 2006, 21 (5), 375–378. (111) Roozenbeek, B.; Maas, A. I. R.; Menon, D. K. Changing Patterns in the Epidemiology of Traumatic Brain Injury. Nat. Rev. Neurol. 2013, 9 (4), 231–236. https://doi.org/10.1038/nrneurol.2013.22.


Page 42 of 68

Page 43 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(112) Araki, T.; Yokota, H.; Morita, A. Pediatric Traumatic Brain Injury: Characteristic Features, Diagnosis, and Management. Neurol. Med. Chir. (Tokyo). 2017, 57 (2), 82–93. https://doi.org/10.2176/nmc.ra.2016-0191. (113) Collins, N. C.; Molcho, M.; Carney, P.; McEvoy, L.; Geoghegan, L.; Phillips, J. P.; Nicholson, A. J. Are Boys and Girls That Different? An Analysis of Traumatic Brain Injury in Children. Emerg. Med.

J. 2013, 30 (8), 675–678. https://doi.org/10.1136/emermed-2011-200496. (114) Susman, M.; DiRusso, S. M.; Sullivan, T.; Risucci, D.; Nealon, P.; Cuff, S.; Benzil, D. Traumatic Brain Injury in the Elderly: Increased Mortality and Worse Functional Outcome at Discharge despite Lower Injury Severity. J. Trauma 2002, 53 (2), 219–224. https://doi.org/10.1097/00005373200208000-00004. (115) LeBlanc, J.; Guise, E. de; Gosselin, N.; Feyz, M. Comparison of Functional Outcome Following Acute Care in Young, Middle-Aged and Elderly Patients with Traumatic Brain Injury. Brain Inj. 2006, 20 (8), 779–790. https://doi.org/10.1080/02699050600831835. (116) Hautzinger, S.; Howell, A.; Scandlyn, J.; Wool, Z. H. US Veterans & Military Families: Cost of War http://watson.brown.edu/costsofwar/costs/human/veterans (accessed Sep 22, 2017). (117) Hoge, C. W.; Castro, C. A.; Yurgil, K. A.; Barkauskas, D. A.; Vasterling, J. J.; Nievergelt, C. M.; Larson, G. E.; Schork, N. J.; Litz, B. T.; Nash, W. P.; et al. Treatment of Generalized War-Related Health Concerns Placing TBI and PTSD in Context. JAMA - Journal of the American Medical

Association. American Medical Association October 22, 2014, pp 1685–1686. https://doi.org/10.1001/jama.2014.6670. (118) Terrio, H.; Brenner, L. A.; Ivins, B. J.; Cho, J. M.; Helmick, K.; Schwab, K.; Scally, K.; Bretthauer, R.; Warden, D. Traumatic Brain Injury Screening: Preliminary Findings in a US Army Brigade Combat Team. J. Head Trauma Rehabil. 2009, 24 (1), 14–23. https://doi.org/10.1097/HTR.0b013e31819581d8. (119) Tanielian, T.; Jaycox, L. H.; editors. Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery, 2008. (120) Defense and Veterans Brain Injury Center. DoD Worldwide Numbers for TBI http://dvbic.dcoe.mil/dod-worldwide-numbers-tbi (accessed Sep 22, 2017). (121) Defense and Veterans Brain Injury Center. Medical Provider Screening and Diagnostic Coding

Rehabilitation Provider Diagnostic Coding ICD-10 Coding Guidance for Traumatic Brain Injury Severity of TBI; 2015. (122) Regasa, L. E.; Michael Thomas, D.; Gill, R. S.; Marion, D. W.; Ivins, B. J. Military Deployment May Increase the Risk for Traumatic Brain Injury Following Deployment. J. Head Trauma Rehabil. 2016, 31 (1), E28–E35. https://doi.org/10.1097/HTR.0000000000000155. (123) Williams, V. F.; Stahlman, S.; Hunt, D. J.; O’Donnell, F. L. Diagnoses of Traumatic Brain Injury Not Clearly Associated with Deployment, Active Component, U.S. Armed Forces, 2001-2016. MSMR 2017, 24 (3), 2–8.



(124) Gardner, R. C.; Byers, A.; Barnes, D. E.; Li, Y.; Boscardin, J.; Yaffe, K. Mild Traumatic Brain Injury Is Associated with Increased Risk of Parkinson Disease in Military Veterans: A Chronic Effects of Neurotrauma Consortium Study. Neurology 2017, 88 (16 Supplement 1). (125) Barnes, D. E.; Kaup, A.; Kirby, K. A.; Byers, A. L.; Diaz-Arrastia, R.; Yaffe, K. Traumatic Brain Injury and Risk of Dementia in Older Veterans. Neurology 2014, 83 (4), 312–319. https://doi.org/10.1212/WNL.0000000000000616. (126) Jones, E.; Fear, N. T.; Wessely, S. Shell Shock and Mild Traumatic Brain Injury: A Historical Review. American Journal of Psychiatry. American Psychiatric Association November 1, 2007, pp 1641–1645. https://doi.org/10.1176/appi.ajp.2007.07071180. (127) Tsao, J. W.; Stentz, L. A.; Rouhanian, M.; Howard, R. S.; Perry, B. N.; Haran, F. J.; Pasquina, P. F.; Wolde, M.; Taylor, C. E.; Lizardo, R.; et al. Effect of Concussion and Blast Exposure on Symptoms after Military Deployment. Neurology 2017, 89 (19), 2010–2016. https://doi.org/10.1212/WNL.0000000000004616. (128) Smith, D. H.; Johnson, V. E.; Stewart, W. Chronic Neuropathologies of Single and Repetitive TBI: Substrates of Dementia? Nat. Rev. Neurol. 2013, 9 (4), 211–221. https://doi.org/10.1038/nrneurol.2013.29. (129) Rosenfeld, J. V; McFarlane, A. C.; Bragge, P.; Armonda, R. A.; Grimes, J. B.; Ling, G. S. BlastRelated Traumatic Brain Injury. The Lancet Neurology. Elsevier September 1, 2013, pp 882–893. https://doi.org/10.1016/S1474-4422(13)70161-3. (130) Duckworth, J. L.; Grimes, J.; Ling, G. S. F. Pathophysiology of Battlefield Associated Traumatic Brain Injury. Pathophysiology 2013, 20 (1), 23–30. https://doi.org/10.1016/j.pathophys.2012.03.001. (131) McKee, A. C.; Robinson, M. E. Military-Related Traumatic Brain Injury and Neurodegeneration.

Alzheimer’s Dement. 2014, 10 (3 SUPPL.), S242–S253. https://doi.org/10.1016/j.jalz.2014.04.003. (132) Nemetz, P. N.; Leibson, C.; Naessens, J. M.; Beard, M.; Kokmen, E.; Annegers, J. F.; Kurland, L. T. Traumatic Brain Injury and Time to Onset of Alzheimer’s Disease: A Population-Based Study.

Am. J. Epidemiol. 1999, 149 (1), 32–40. https://doi.org/10.1093/oxfordjournals.aje.a009724. (133) Boussard, C. N.; Holm, L. W.; Cancelliere, C.; Godbolt, A. K.; Boyle, E.; Stålnacke, B.-M.; Hincapié, C. A.; Cassidy, J. D.; Borg, J. Nonsurgical Interventions After Mild Traumatic Brain Injury: A Systematic Review. Results of the International Collaboration on Mild Traumatic Brain Injury Prognosis. Arch. Phys. Med. Rehabil. 2014, 95 (3S), S257–S264. https://doi.org/10.1016/j.apmr.2013.10.009. (134) Levin, H. S.; Diaz-Arrastia, R. R. Diagnosis, Prognosis, and Clinical Management of Mild Traumatic Brain Injury. Lancet Neurol. 2015, 14 (5), 506–517. https://doi.org/10.1016/S14744422(15)00002-2. (135) Teasdale, G.; Maas, A.; Lecky, F.; Manley, G.; Stocchetti, N.; Murray, G. The Glasgow Coma Scale at 40 Years: Standing the Test of Time. The Lancet Neurology. Elsevier August 1, 2014, pp


Page 44 of 68

Page 45 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


844–854. https://doi.org/10.1016/S1474-4422(14)70120-6. (136) Salottolo, K.; Stewart Levy, A.; Slone, D. S.; Mains, C. W.; Bar-Or, D. The Effect of Age on Glasgow Coma Scale Score in Patients with Traumatic Brain Injury. JAMA Surg. 2014, 149 (7), 727–734. https://doi.org/10.1001/jamasurg.2014.13. (137) Kehoe, A.; Rennie, S.; Smith, J. E. Glasgow Coma Scale Is Unreliable for the Prediction of Severe Head Injury in Elderly Trauma Patients. Emerg. Med. J. 2015, 32 (8), 613–615. https://doi.org/10.1136/emermed-2013-203488. (138) Karnati, H. K.; Garcia, J. H.; Tweedie, D.; Becker, R. E.; Kapogiannis, D.; Greig, N. H. Neuronal Enriched Extracellular Vesicle Proteins as Biomarkers for Brain Traumatic Injury. J. Neurotrauma 2018, neu.2018.5898. https://doi.org/10.1089/neu.2018.5898. (139) Zetterberg, H.; Smith, D. H.; Blennow, K. Biomarkers of Mild Traumatic Brain Injury in Cerebrospinal Fluid and Blood. Nat. Rev. Neurol. 2013, 9 (4), 201–210. https://doi.org/10.1038/nrneurol.2013.9. (140) Podell, J.; Korley, F.; Yue, J.; Wilson, D.; Ferguson, A.; Yuh, E.; Mukherjee, P.; Wang, K.; Valadka, A.; Puccio, A.; et al. Acute Serum GFAP, NF-L, Tau, and UCH-L1 Predict CT Pathology and 3-Month Outcome in TBI (S42.004). Neurology 2018, 90 (15 Supplement). (141) Chen, S. T.; Siddarth, P.; Merrill, D. A.; Martinez, J.; Emerson, N. D.; Liu, J.; Wong, K.-P.; Satyamurthy, N.; Giza, C. C.; Huang, S.-C.; et al. FDDNP-PET Tau Brain Protein Binding Patterns in Military Personnel with Suspected Chronic Traumatic Encephalopathy. J. Alzheimer’s Dis. 2018,

65, 79–88. https://doi.org/10.3233/JAD-171152. (142) Samson, K. In the Clinic-Traumatic Brain Injury: FDA Approves First Blood Test for Brain Bleeds After Mild TBI/Concussion. Neurol. Today 2018, 18 (6), 12–18. https://doi.org/10.1097/01.NT.0000532091.01255.0b. (143) Bazarian, J. J.; Biberthaler, P.; Welch, R. D.; Lewis, L. M.; Barzo, P.; Bogner-Flatz, V.; Gunnar Brolinson, P.; Büki, A.; Chen, J. Y.; Christenson, R. H.; et al. Serum GFAP and UCH-L1 for Prediction of Absence of Intracranial Injuries on Head CT (ALERT-TBI): A Multicentre Observational Study. Lancet Neurol. 2018, 17 (9), 782–789. https://doi.org/10.1016/S14744422(18)30231-X. (144) Corps, K. N.; Roth, T. L.; McGavern, D. B. Inflammation and Neuroprotection in Traumatic Brain Injury. JAMA Neurol. 2015, 72 (3), 355–362. https://doi.org/10.1001/jamaneurol.2014.3558. (145) Bigler, E. D. Traumatic Brain Injury, Neuroimaging, and Neurodegeneration. Front. Hum. Neurosci. 2013, 7, 395. https://doi.org/10.3389/fnhum.2013.00395. (146) Ramlackhansingh, A. F.; Brooks, D. J.; Greenwood, R. J.; Bose, S. K.; Turkheimer, F. E.; Kinnunen, K. M.; Gentleman, S.; Heckemann, R. A.; Gunanayagam, K.; Gelosa, G.; et al. Inflammation after Trauma: Microglial Activation and Traumatic Brain Injury. Ann. Neurol. 2011, 70 (3), 374–383. https://doi.org/10.1002/ana.22455. (147) Andriessen, T. M. J. C.; Jacobs, B.; Vos, P. E. Clinical Characteristics and Pathophysiological



Mechanisms of Focal and Diffuse Traumatic Brain Injury. J. Cell. Mol. Med. 2010, 14 (10), 2381– 2392. https://doi.org/10.1111/j.1582-4934.2010.01164.x. (148) Mckee, C. A.; Lukens, J. R. Emerging Roles for the Immune System in Traumatic Brain Injury.

Front. Immunol 2016, 7 (7), 556. https://doi.org/10.3389/fimmu.2016.00556. (149) Bianchi, M. E. DAMPs, PAMPs and Alarmins: All We Need to Know about Danger. J. Leukoc. Biol. 2006, 81 (1), 1–5. https://doi.org/10.1189/jlb.0306164. (150) Manson, J.; Thiemermann, C.; Brohi, K. Trauma Alarmins as Activators of Damage-Induced Inflammation. British Journal of Surgery. January 2012, pp 12–20. https://doi.org/10.1002/bjs.7717. (151) Jassam, Y. N.; Izzy, S.; Whalen, M.; McGavern, D. B.; El Khoury, J. Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift. Neuron. Cell Press September 13, 2017, pp 1246–1265. https://doi.org/10.1016/j.neuron.2017.07.010. (152) Nimmerjahn, A.; Kirchhoff, F.; Helmchen, F. Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo. Science (80-. ). 2005, 308 (5726), 1314–1318. https://doi.org/10.1126/science.1110647. (153) Mosser, D. M.; Edwards, J. P. Exploring the Full Spectrum of Macrophage Activation. Nature

Reviews Immunology. NIH Public Access December 2008, pp 958–969. https://doi.org/10.1038/nri2448. (154) Ransohoff, R. M. A Polarizing Question: Do M1 and M2 Microglia Exist. Nature Neuroscience. Nature Publishing Group August 1, 2016, pp 987–991. https://doi.org/10.1038/nn.4338. (155) Hammond, T. R.; Dufort, C.; Dissing-Olesen, L.; Giera, S.; Young, A.; Wysoker, A.; Walker, A. J.; Gergits, F.; Segel, M.; Nemesh, J.; et al. Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity 2018. https://doi.org/10.1016/J.IMMUNI.2018.11.004. (156) De Biase, L. M.; Schuebel, K. E.; Fusfeld, Z. H.; Jair, K.; Hawes, I. A.; Cimbro, R.; Zhang, H. Y.; Liu, Q. R.; Shen, H.; Xi, Z. X.; et al. Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia. Neuron 2017, 95 (2), 341–356.e6. https://doi.org/10.1016/j.neuron.2017.06.020. (157) Doorn, K. J.; Breve, J. J. P.; Drukarch, B.; Boddeke, H. W.; Huitinga, I.; Lucassen, P. J.; van Dam, A.-M. Brain Region-Specific Gene Expression Profiles in Freshly Isolated Rat Microglia. Front.

Cell. Neurosci. 2015, 9, 84. https://doi.org/10.3389/fncel.2015.00084. (158) Donat, C. K.; Scott, G.; Gentleman, S. M.; Sastre, M. Microglial Activation in Traumatic Brain Injury. Frontiers in Aging Neuroscience. Frontiers Media SA 2017, p 208. https://doi.org/10.3389/fnagi.2017.00208. (159) Hoogland, I. C. M.; Houbolt, C.; van Westerloo, D. J.; van Gool, W. A.; van de Beek, D. Systemic Inflammation and Microglial Activation: Systematic Review of Animal Experiments. Journal of

Neuroinflammation. BioMed Central June 6, 2015, p 114. https://doi.org/10.1186/s12974-015-


Page 46 of 68

Page 47 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0332-6. (160) Johnson, V. E.; Stewart, J. E.; Begbie, F. D.; Trojanowski, J. Q.; Smith, D. H.; Stewart, W. Inflammation and White Matter Degeneration Persist for Years after a Single Traumatic Brain Injury. Brain 2013, 136 (Pt 1), 28–42. https://doi.org/10.1093/brain/aws322. (161) Loane, D. J.; Kumar, A.; Stoica, B. A.; Cabatbat, R.; Faden, A. I. Progressive Neurodegeneration after Experimental Brain Trauma: Association with Chronic Microglial Activation. J. Neuropathol.

Exp. Neurol. 2014, 73 (1), 14–29. https://doi.org/10.1097/NEN.0000000000000021. (162) Nagamoto-Combs, K.; McNeal, D. W.; Morecraft, R. J.; Combs, C. K. Prolonged Microgliosis in the Rhesus Monkey Central Nervous System after Traumatic Brain Injury. J. Neurotrauma 2007, 24 (11), 1719–1742. https://doi.org/10.1089/neu.2007.0377. (163) Scott, G.; Hellyer, P. J.; Ramlackhansingh, A. F.; Brooks, D. J.; Matthews, P. M.; Sharp, D. J. Thalamic Inflammation after Brain Trauma Is Associated with Thalamo-Cortical White Matter Damage. J. Neuroinflammation 2015, 12, 224. https://doi.org/10.1186/s12974-015-0445-y. (164) Cagnin, A.; Brooks, D. J.; Kennedy, A. M.; Gunn, R. N.; Myers, R.; Turkheimer, F. E.; Jones, T.; Banati, R. B. In-Vivo Measurement of Activated Microglia in Dementia. Lancet 2001, 358 (9280), 461–467. https://doi.org/10.1016/S0140-6736(01)05625-2. (165) Perry, V. H.; Holmes, C. Microglial Priming in Neurodegenerative Disease. Nature Reviews

Neurology. Nature Publishing Group April 18, 2014, pp 217–224. https://doi.org/10.1038/nrneurol.2014.38. (166) Norden, D. M.; Muccigrosso, M. M.; Godbout, J. P. Microglial Priming and Enhanced Reactivity to Secondary Insult in Aging, and Traumatic CNS Injury, and Neurodegenerative Disease.

Neuropharmacology 2015, 96 (Pt A), 29–41. https://doi.org/10.1016/j.neuropharm.2014.10.028. (167) Perry, V. H.; Newman, T. A.; Cunningham, C. The Impact of Systemic Infection on the Progression of Neurodegenerative Disease. Nat. Rev. Neurosci. 2003, 4 (2), 103–112. https://doi.org/10.1038/nrn1032. (168) Witcher, K. G.; Eiferman, D. S.; Godbout, J. P. Priming the Inflammatory Pump of the CNS after Traumatic Brain Injury. Trends Neurosci. 2015, 38 (10), 609–620. https://doi.org/10.1016/J.TINS.2015.08.002. (169) Trapp, B. D.; Wujek, J. R.; Criste, G. A.; Jalabi, W.; Yin, X.; Kidd, G. J.; Stohlman, S.; Ransohoff, R. Evidence for Synaptic Stripping by Cortical Microglia. Glia 2007, 55 (4), 360–368. https://doi.org/10.1002/glia.20462. (170) Elmore, M. R. P.; Hohsfield, L. A.; Kramár, E. A.; Soreq, L.; Lee, R. J.; Pham, S. T.; Najafi, A. R.; Spangenberg, E. E.; Wood, M. A.; West, B. L.; et al. Replacement of Microglia in the Aged Brain Reverses Cognitive, Synaptic, and Neuronal Deficits in Mice. Aging Cell. Wiley-Blackwell December 2018, p e12832. https://doi.org/10.1111/acel.12832. (171) Simon, D. W.; McGeachy, M. J.; Baylr, H.; Clark, R. S. B.; Loane, D. J.; Kochanek, P. M. The FarReaching Scope of Neuroinflammation after Traumatic Brain Injury. Nature Reviews Neurology.



Nature Publishing Group March 10, 2017, pp 171–191. https://doi.org/10.1038/nrneurol.2017.13. (172) Elmore, M. R. P.; Najafi, A. R.; Koike, M. A.; Dagher, N. N.; Spangenberg, E. E.; Rice, R. A.; Kitazawa, M.; Matusow, B.; Nguyen, H.; West, B. L.; et al. Colony-Stimulating Factor 1 Receptor Signaling Is Necessary for Microglia Viability, Unmasking a Microglia Progenitor Cell in the Adult Brain. Neuron 2014, 82 (2), 380–397. https://doi.org/10.1016/j.neuron.2014.02.040. (173) Rice, R. A.; Pham, J.; Lee, R. J.; Najafi, A. R.; West, B. L.; Green, K. N. Microglial Repopulation Resolves Inflammation and Promotes Brain Recovery after Injury. Glia 2017, 65 (6), 931–944. https://doi.org/10.1002/glia.23135. (174) Neil, S. M. O.; Witcher, K. G.; Mckim, D. B.; Godbout, J. P. Forced Turnover of Aged Microglia Induces an Intermediate Phenotype but Does Not Rebalance CNS Environmental Cues Driving Priming to Immune Challenge. Acta Neuropathol. Commun. 2018, 8 (1), 1–20. https://doi.org/10.1186/s40478-018-0636-8. (175) Han, J.; Zhu, K.; Zhang, X. M.; Harris, R. A. Enforced Microglial Depletion and Repopulation as a Promising Strategy for the Treatment of Neurological Disorders. Glia 2018, 1–15. https://doi.org/10.1002/glia.23529. (176) Witcher, K. G.; Bray, C. E.; Dziabis, J. E.; McKim, D. B.; Benner, B. N.; Rowe, R. K.; KokikoCochran, O. N.; Popovich, P. G.; Lifshitz, J.; Eiferman, D. S.; et al. Traumatic Brain Injury-Induced Neuronal Damage in the Somatosensory Cortex Causes Formation of Rod-Shaped Microglia That Promote Astrogliosis and Persistent Neuroinflammation. Glia 2018, 66 (12), 2719–2736. https://doi.org/10.1002/glia.23523. (177) Woodcock, T.; Morganti-Kossmann, M. C. The Role of Markers of Inflammation in Traumatic Brain Injury. Front. Neurol. 2013, 4 MAR, 18. https://doi.org/10.3389/fneur.2013.00018. (178) Das, M.; Mohapatra, S.; Mohapatra, S. S. New Perspectives on Central and Peripheral Immune Responses to Acute Traumatic Brain Injury. Journal of Neuroinflammation. BioMed Central October 12, 2012, p 236. https://doi.org/10.1186/1742-2094-9-236. (179) Loane, D. J.; Kumar, A. Microglia in the TBI Brain: The Good, the Bad, and the Dysregulated.

Experimental Neurology. NIH Public Access January 2016, pp 316–327. https://doi.org/10.1016/j.expneurol.2015.08.018. (180) Hammad, A.; Westacott, L.; Zaben, M. The Role of the Complement System in Traumatic Brain Injury: A Review. Journal of Neuroinflammation. BioMed Central January 22, 2018, p 24. https://doi.org/10.1186/s12974-018-1066-z. (181) Bellander, B.-M.; Singhrao, S. K.; Ohlsson, M.; Mattsson, P.; Svensson, M. Complement Activation in the Human Brain after Traumatic Head Injury. J. Neurotrauma 2001, 18 (12), 1295– 1311. https://doi.org/10.1089/08977150152725605. (182) De Blasio, D.; Fumagalli, S.; Orsini, F.; Neglia, L.; Perego, C.; Ortolano, F.; Zanier, E. R.; Picetti, E.; Locatelli, M.; Stocchetti, N.; et al. Human Brain Trauma Severity Is Associated with Lectin Complement Pathway Activation. J. Cereb. Blood Flow Metab. 2018, 0271678X1875888.


Page 48 of 68

Page 49 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


https://doi.org/10.1177/0271678X18758881. (183) Leinhase, I.; Schmidt, O. I.; Thurman, J. M.; Hossini, A. M.; Rozanski, M.; Taha, M. E.; Scheffler, A.; John, T.; Smith, W. R.; Holers, V. M.; et al. Pharmacological Complement Inhibition at the C3 Convertase Level Promotes Neuronal Survival, Neuroprotective Intracerebral Gene Expression, and Neurological Outcome after Traumatic Brain Injury. Exp. Neurol. 2006, 199 (2), 454–464. https://doi.org/10.1016/J.EXPNEUROL.2006.01.033. (184) Sewell, D. L.; Nacewicz, B.; Liu, F.; Macvilay, S.; Erdei, A.; Lambris, J. D.; Sandor, M.; Fabry, Z. Complement C3 and C5 Play Critical Roles in Traumatic Brain Cryoinjury: Blocking Effects on Neutrophil Extravasation by C5a Receptor Antagonist. J. Neuroimmunol. 2004, 155 (1–2), 55–63. https://doi.org/10.1016/j.jneuroim.2004.06.003. (185) Liddelow, S. A.; Guttenplan, K. A.; Clarke, L. E.; Bennett, F. C.; Bohlen, C. J.; Schirmer, L.; Bennett, M. L.; Münch, A. E.; Chung, W. S.; Peterson, T. C.; et al. Neurotoxic Reactive Astrocytes Are Induced by Activated Microglia. Nature 2017, 541 (7638), 481–487. https://doi.org/10.1038/nature21029. (186) Clarke, L. E.; Liddelow, S. A.; Chakraborty, C.; Münch, A. E.; Heiman, M.; Barres, B. A. Normal Aging Induces A1-like Astrocyte Reactivity. Proc. Natl. Acad. Sci. 2018, 115 (8), E1896–E1905. https://doi.org/10.1073/pnas.1800165115. (187) Alawieh, A.; Langley, E. F.; Weber, S.; Adkins, D.; Tomlinson, S. Identifying the Role of Complement in Triggering Neuroinflammation after Traumatic Brain Injury. J. Neurosci. 2018, 38 (10), 2197–17. https://doi.org/10.1523/JNEUROSCI.2197-17.2018. (188) Shi, Q.; Colodner, K. J.; Matousek, S. B.; Merry, K.; Hong, S.; Kenison, J. E.; Frost, J. L.; Le, K. X.; Li, S.; Dodart, J.-C.; et al. Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline. J. Neurosci. 2015, 35 (38), 13029–13042. https://doi.org/10.1523/JNEUROSCI.1698-15.2015. (189) Krukowski, K.; Chou, A.; Feng, X.; Tiret, B.; Paladini, M.-S.; Riparip, L.-K.; Chaumeil, M.; Lemere, C.; Rosi, S. Traumatic Brain Injury in Aged Mice Induces Chronic Microglia Activation, Synapse Loss, and Complement-Dependent Memory Deficits. Int. J. Mol. Sci. 2018, 19 (12), 3753. https://doi.org/10.3390/ijms19123753. (190) Habbas, S.; Santello, M.; Becker, D.; Stubbe, H.; Zappia, G.; Liaudet, N.; Klaus, F. R.; Kollias, G.; Fontana, A.; Pryce, C. R.; et al. Neuroinflammatory TNFα Impairs Memory via Astrocyte Signaling.

Cell 2015, 163 (7), 1730–1741. https://doi.org/10.1016/j.cell.2015.11.023. (191) Scherbel, U.; Raghupathi, R.; Nakamura, M.; Saatman, K. E.; Trojanowski, J. Q.; Neugebauer, E.; Marino, M. W.; McIntosh, T. K. Differential Acute and Chronic Responses of Tumor Necrosis Factor-Deficient Mice to Experimental Brain Injury. Proc. Natl. Acad. Sci. U. S. A. 1999, 96 (15), 8721–8726. https://doi.org/10.1073/PNAS.96.15.8721. (192) Burda, J. E.; Bernstein, A. M.; Sofroniew, M. V. Astrocyte Roles in Traumatic Brain Injury.

Experimental Neurology. January 2016, pp 305–315.



https://doi.org/10.1016/j.expneurol.2015.03.020. (193) Hol, E. M.; Pekny, M. Glial Fibrillary Acidic Protein (GFAP) and the Astrocyte Intermediate Filament System in Diseases of the Central Nervous System. Current Opinion in Cell Biology. Elsevier Current Trends February 1, 2015, pp 121–130. https://doi.org/10.1016/j.ceb.2015.02.004. (194) Liddelow, S. A.; Barres, B. A. Reactive Astrocytes: Production, Function, and Therapeutic Potential. Immunity. 2017, pp 957–967. https://doi.org/10.1016/j.immuni.2017.06.006. (195) Gardner, R. C.; Rubenstein, R.; Wang, K. K. W.; Korley, F. K.; Yue, J. K.; Yuh, E. L.; Mukherje, P.; Valadka, A. B.; Okonkwo, D. O.; Diaz-Arrastia, R.; et al. Age-Related Differences in Diagnostic Accuracy of Plasma Glial Fibrillary Acidic Protein and Tau for Identifying Acute Intracranial Trauma on Computed Tomography: A TRACK-TBI Study. J. Neurotrauma 2018, 35 (20), neu.2018.5694. https://doi.org/10.1089/neu.2018.5694. (196) Bush, T. G.; Puvanachandra, N.; Horner, C. H.; Polito, A.; Ostenfeld, T.; Svendsen, C. N.; Mucke, L.; Johnson, M. H.; Sofroniew, M. V. Leukocyte Infiltration, Neuronal Degeneration, and Neurite Outgrowth after Ablation of Scar-Forming, Reactive Astrocytes in Adult Transgenic Mice. Neuron 1999, 23 (2), 297–308. https://doi.org/10.1016/S0896-6273(00)80781-3. (197) Werner, C.; Engelhard, K. Pathophysiology of Traumatic Brain Injury. Br. J. Anaesth. 2007, 99 (1), 4–9. https://doi.org/10.1093/bja/aem131. (198) Palmer, A. M.; Marion, D. W.; Botscheller, M. L.; Swedlow, P. E.; Styren, S. D.; DeKosky, S. T. Traumatic Brain Injury-Induced Excitotoxicity Assessed in a Controlled Cortical Impact Model. J.

Neurochem. 1993, 61 (6), 2015–2024. https://doi.org/10.1111/j.1471-4159.1993.tb07437.x. (199) Bullock, R.; Zauner, A.; Myseros, J. S.; Marmarou, A.; Woodward, J. J.; Young, H. F. Evidence for Prolonged Release of Excitatory Amino Acids in Severe Human Head Trauma: Relationship to Clinical Events. Ann. N. Y. Acad. Sci. 1995, 765 (1), 290–297. https://doi.org/10.1111/j.17496632.1995.tb16586.x. (200) Hutchinson, P. J. Microdialysis in Traumatic Brain Injury - Methodology and Pathophysiology. Acta

Neurochir. Suppl. 2005, No. 95, 441–445. https://doi.org/10.1007/3-211-32318-X_91. (201) Chen, Y.; Swanson, R. A. Astrocytes and Brain Injury. Journal of Cerebral Blood Flow and

Metabolism. February 2003, pp 137–149. https://doi.org/10.1097/01.WCB.0000044631.80210.3C. (202) Raghavendra Rao, V. L.; Başkaya, M. K.; Doğan, A.; Rothstein, J. D.; Dempsey, R. J. Traumatic Brain Injury Down-Regulates Glial Glutamate Transporter (GLT-1 and GLAST) Proteins in Rat Brain. J. Neurochem. 2002, 70 (5), 2020–2027. https://doi.org/10.1046/j.14714159.1998.70052020.x. (203) Landeghem, F. K. H. Van; Weiss, T.; Oehmichen, M.; Deimling, A. Von. Decreased Expression of Glutamate Transporters in Astrocytes after Human Traumatic Brain Injury. J. Neurotrauma 2006,

23 (10), 1518–1528. https://doi.org/10.1089/neu.2006.23.1518. (204) Beschorner, R.; Dietz, K.; Schauer, N.; Mittelbronn, M.; Schluesener, H. J.; Trautmann, K.; Meyermann, R.; Simon, P. Expression of EAAT1 Reflects a Possible Neuroprotective Function of


Page 50 of 68

Page 51 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Reactive Astrocytes and Activated Microglia Following Human Traumatic Brain Injury. Histol.

Histopathol. 2007, 22 (4–6), 515–526. https://doi.org/10.14670/HH-22.515. (205) Bezzi, P.; Domercq, M.; Brambilla, L.; Galli, R.; Schols, D.; De Clercq, E.; Vescovi, A.; Bagetta, G.; Kollias, G.; Meldolesi, J.; et al. CXCR4-Activated Astrocyte Glutamate Release via TNFa: Amplification by Microglia Triggers Neurotoxicity. Nat. Neurosci. 2001, 4 (7), 702–710. https://doi.org/10.1038/89490. (206) Santello, M.; Bezzi, P.; Volterra, A. TNFα Controls Glutamatergic Gliotransmission in the Hippocampal Dentate Gyrus. Neuron 2011, 69 (5), 988–1001. https://doi.org/10.1016/j.neuron.2011.02.003. (207) Takeuchi, H.; Jin, S.; Wang, J.; Zhang, G.; Kawanokuchi, J.; Kuno, R.; Sonobe, Y.; Mizuno, T.; Suzumura, A. Tumor Necrosis Factor-α Induces Neurotoxicity via Glutamate Release from Hemichannels of Activated Microglia in an Autocrine Manner. J. Biol. Chem. 2006, 281 (30), 21362–21368. https://doi.org/10.1074/jbc.M600504200. (208) Chen, C.-J.; OU, Y.-C.; Chang, C.-Y.; Pan, H.-C.; Liao, S.-L.; Chen, S.-Y.; Raung, S.-L.; Lai, C.-Y. Glutamate Released by Japanese Encephalitis Virus-Infected Microglia Involves TNF-α Signaling and Contributes to Neuronal Death. Glia 2012, 60 (3), 487–501. https://doi.org/10.1002/glia.22282. (209) Ye, L.; Huang, Y.; Zhao, L.; Li, Y.; Sun, L.; Zhou, Y.; Qian, G.; Zheng, J. C. IL-1β and TNF-α Induce Neurotoxicity through Glutamate Production: A Potential Role for Neuronal Glutaminase. J.

Neurochem. 2013, 125 (6), 897–908. https://doi.org/10.1111/jnc.12263. (210) Clark, I. A.; Vissel, B. Excess Cerebral TNF Causing Glutamate Excitotoxicity Rationalizes Treatment of Neurodegenerative Diseases and Neurogenic Pain by Anti-TNF Agents. J.

Neuroinflammation 2016, 13 (1), 236. https://doi.org/10.1186/s12974-016-0708-2. (211) Frankola, K. A.; H. Greig, N.; Luo, W.; Tweedie, D. Targeting TNF-Alpha to Elucidate and Ameliorate Neuroinflammation in Neurodegenerative Diseases. CNS Neurol. Disord. - Drug

Targets 2011, 10 (3), 391–403. https://doi.org/10.2174/187152711794653751. (212) Arundine, M.; Tymianski, M. Molecular Mechanisms of Calcium-Dependent Neurodegeneration in Excitotoxicity. Cell Calcium. Churchill Livingstone October 1, 2003, pp 325–337. https://doi.org/10.1016/S0143-4160(03)00141-6. (213) Fujikawa, D. G. The Role of Excitotoxic Programmed Necrosis in Acute Brain Injury.

Computational and Structural Biotechnology Journal. Elsevier January 1, 2015, pp 212–221. https://doi.org/10.1016/j.csbj.2015.03.004. (214) Nixon, R. A. The Calpains in Aging and Aging-Related Diseases. Ageing Research Reviews. Elsevier October 1, 2003, pp 407–418. https://doi.org/10.1016/S1568-1637(03)00029-1. (215) Ha, H. C.; Snyder, S. H. Poly(ADP-Ribose) Polymerase-1 in the Nervous System. Neurobiology of

Disease. Academic Press August 1, 2000, pp 225–239. https://doi.org/10.1006/nbdi.2000.0324. (216) Besson, V. C.; Croci, N.; Boulu, R. G.; Plotkine, M.; Marchand-Verrecchia, C. Deleterious Poly(ADP-Ribose)Polymerase-1 Pathway Activation in Traumatic Brain Injury in Rat. Brain Res.



2003, 989 (1), 58–66. https://doi.org/10.1016/S0006-8993(03)03362-6. (217) Stoica, B. A.; Loane, D. J.; Zhao, Z.; Kabadi, S. V.; Hanscom, M.; Byrnes, K. R.; Faden, A. I. PARP-1 Inhibition Attenuates Neuronal Loss, Microglia Activation and Neurological Deficits after Traumatic Brain Injury. J. Neurotrauma 2014, 31 (8), 758–772. https://doi.org/10.1089/neu.2013.3194. (218) Whalen, M. J.; Clark, R. S. B.; Dixon, C. E.; Robichaud, P.; Marion, D. W.; Vagni, V.; Graham, S. H.; Virag, L.; Hasko, G.; Stachlewitz, R.; et al. Reduction of Cognitive and Motor Deficits after Traumatic Brain Injury in Mice Deficient in Poly(ADP-Ribose) Polymerase. J. Cereb. Blood Flow

Metab. 1999, 19 (8), 835–842. https://doi.org/10.1097/00004647-199908000-00002. (219) Ang, B. T.; Yap, E.; Lim, J.; Tan, W. L.; Ng, P. Y.; Ng, I.; Yeo, T. T. Poly(Adenosine DiphosphateRibose) Polymerase Expression in Human Traumatic Brain Injury. J Neurosurg 2003, 99 (1), 125– 130. https://doi.org/10.3171/jns.2003.99.1.0125. (220) d’Avila, J. C.; Lam, T. I.; Bingham, D.; Shi, J.; Won, S. J.; Kauppinen, T. M.; Massa, S.; Liu, J.; Swanson, R. A. Microglial Activation Induced by Brain Trauma Is Suppressed by Post-Injury Treatment with a PARP Inhibitor. J. Neuroinflammation 2012, 9 (1), 521. https://doi.org/10.1186/1742-2094-9-31. (221) Kauppinen, T. M.; Swanson, R. A. Poly(ADP-Ribose) Polymerase-1 Promotes Microglial Activation, Proliferation, and Matrix Metalloproteinase-9-Mediated Neuron Death. J. Immunol. 2005, 174 (4), 2288–2296. https://doi.org/10.4049/JIMMUNOL.174.4.2288. (222) Piao, C.-S.; Loane, D. J.; Stoica, B. A.; Li, S.; Hanscom, M.; Cabatbat, R.; Blomgren, K.; Faden, A. I. Combined Inhibition of Cell Death Induced by Apoptosis Inducing Factor and Caspases Provides Additive Neuroprotection in Experimental Traumatic Brain Injury. Neurobiol. Dis. 2012, 46 (3), 745–758. https://doi.org/10.1016/j.nbd.2012.03.018. (223) Hong, S. J.; Dawson, T. M.; Dawson, V. L. Nuclear and Mitochondrial Conversations in Cell Death: PARP-1 and AIF Signaling. Trends in Pharmacological Sciences. Elsevier Current Trends May 1, 2004, pp 259–264. https://doi.org/10.1016/j.tips.2004.03.005. (224) Kruman, I. I. Why Do Neurons Enter the Cell Cycle? Cell Cycle. Taylor & Francis June 2004, pp 769–773. https://doi.org/10.4161/cc.3.6.901. (225) Kruman, I. I.; Wersto, R. P.; Cardozo-Pelaez, F.; Smilenov, L.; Chan, S. L.; Chrest, F. J.; Emokpae, R.; Gorospe, M.; Mattson, M. P. Cell Cycle Activation Linked to Neuronal Cell Death Initiated by DNA Damage. Neuron 2004, 41 (4), 549–561. https://doi.org/10.1016/S08966273(04)00017-0. (226) Stoica, B. A.; Faden, A. I. Cell Death Mechanisms and Modulation in Traumatic Brain Injury.

Neurotherapeutics 2010, 7 (1), 3–12. https://doi.org/10.1016/j.nurt.2009.10.023. (227) Di Giovanni, S.; Movsesyan, V.; Ahmed, F.; Cernak, I.; Schinelli, S.; Stoica, B.; Faden, A. I. Cell Cycle Inhibition Provides Neuroprotection and Reduces Glial Proliferation and Scar Formation after Traumatic Brain Injury. Proc. Natl. Acad. Sci. 2005, 102 (23).


Page 52 of 68

Page 53 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


https://doi.org/10.1073/pnas.0500989102. (228) Kabadi, S. V; Stoica, B. A.; Loane, D. J.; Byrnes, K. R.; Hanscom, M.; Cabatbat, R. M.; Tan, M. T.; Faden, A. I. Cyclin D1 Gene Ablation Confers Neuroprotection in Traumatic Brain Injury. J.

Neurotrauma 2012, 29 (5), 813–827. https://doi.org/10.1089/neu.2011.1980. (229) Skovira, J. W.; Wu, J.; Matyas, J. J.; Kumar, A.; Hanscom, M.; Kabadi, S. V; Fang, R.; Faden, A. I.; Di Giovanni, S.; Movsesyan, V.; et al. Cell Cycle Inhibition Reduces Inflammatory Responses, Neuronal Loss, and Cognitive Deficits Induced by Hypobaria Exposure Following Traumatic Brain Injury. J. Neuroinflammation 2016, 13 (1), 299. https://doi.org/10.1186/s12974-016-0769-2. (230) Raghupathi, R.; Graham, D. I.; McIntosh, T. K. Apoptosis After Traumatic Brain Injury. J.

Neurotrauma 2000, 17 (10). https://doi.org/https://doi.org/10.1089/neu.2000.17.927. (231) Juurlink & Phyllis, J.; Paterson, G. G. Review of Oxidative Stress in Brain and Spinal Cord Injury: Suggestions for Pharmacological and Nutritional Management Strategies. J. Spinal Cord Med. 1998, 21 (4), 309–334. https://doi.org/10.1080/10790268.1998.11719540. (232) Plesnila, N.; von Baumgarten, L.; Retiounskaia, M.; Engel, D.; Ardeshiri, A.; Zimmermann, R.; Hoffmann, F.; Landshamer, S.; Wagner, E.; Culmsee, C. Delayed Neuronal Death after Brain Trauma Involves P53-Dependent Inhibition of NF-ΚB Transcriptional Activity. Cell Death Differ. 2007, 14 (8), 1529–1541. https://doi.org/10.1038/sj.cdd.4402159. (233) Yang, L.-Y.; Chu, Y.-H.; Tweedie, D.; Yu, Q.-S.; Pick, C. G.; Hoffer, B. J.; Greig, N. H.; Wang, J.-Y. Post-Trauma Administration of the Pifithrin-α Oxygen Analog Improves Histological and Functional Outcomes after Experimental Traumatic Brain Injury. Exp. Neurol. 2015, 269, 56–66. https://doi.org/10.1016/j.expneurol.2015.03.015. (234) Greig, N. H.; Mattson, M. P.; Perry, T.; Chan, S. L.; Giordano, T.; Sambamurti, K.; Rogers, J. T.; Ovadia, H.; Lahiri, D. K. New Therapeutic Strategies and Drug Candidates for Neurodegenerative Diseases: P53 and TNF-α Inhibitors, and GLP-1 Receptor Agonists. Ann. N. Y. Acad. Sci. 2004,

1035 (1), 290–315. https://doi.org/10.1196/annals.1332.018. (235) Zhu, X.; Yu, Q. sheng; Cutler, R. G.; Culmsee, C. W.; Holloway, H. W.; Lahiri, D. K.; Mattson, M. P.; Greig, N. H. Novel P53 Inactivators with Neuroprotective Action: Syntheses and Pharmacological Evaluation of 2-Imino-2,3,4,5,6,7-Hexahydrobenzothiazole and 2-Imino2,3,4,5,6,7-Hexahydrobenzoxazole Derivatives. J. Med. Chem. 2002, 45 (23), 5090–5097. https://doi.org/10.1021/jm020044d. (236) Gudkov, A. V.; Komarova, E. A. Dangerous Habits of a Security Guard: The Two Faces of P53 as a Drug Target. Human Molecular Genetics. April 15, 2007, pp R67–R72. https://doi.org/10.1093/hmg/ddm052. (237) Gudkov, A. V.; Komarova, E. A. P53 and the Carcinogenicity of Chronic Inflammation. Cold Spring

Harb. Perspect. Med. 2016, 6 (11), a026161. https://doi.org/10.1101/cshperspect.a026161. (238) Yang, L.-Y.; Greig, N. H.; Huang, Y.-N.; Hsieh, T.-H.; Tweedie, D.; Yu, Q.-S.; Hoffer, B. J.; Luo, Y.; Kao, Y.-C.; Wang, J.-Y. Post-Traumatic Administration of the P53 Inactivator Pifithrin-α Oxygen



Analogue Reduces Hippocampal Neuronal Loss and Improves Cognitive Deficits after Experimental Traumatic Brain Injury. Neurobiol. Dis. 2016, 96, 216–226. https://doi.org/10.1016/j.nbd.2016.08.012. (239) Mihara, M.; Erster, S.; Zaika, A.; Petrenko, O.; Chittenden, T.; Pancoska, P.; Moll, U. M. P53 Has a Direct Apoptogenic Role at the Mitochondria. Mol. Cell 2003, 11 (3), 577–590. https://doi.org/10.1016/S1097-2765(03)00050-9. (240) Nakano, K.; Vousden, K. H. PUMA, a Novel Proapoptotic Gene, Is Induced by P53. Mol. Cell 2001, 7 (3), 683–694. https://doi.org/10.1016/S1097-2765(01)00214-3. (241) Krajewska, M.; You, Z.; Rong, J.; Kress, C.; Huang, X.; Yang, J.; Kyoda, T.; Leyva, R.; Banares, S.; Hu, Y.; et al. Neuronal Deletion of Caspase 8 Protects against Brain Injury in Mouse Models of Controlled Cortical Impact and Kainic Acid-Induced Excitotoxicity. PLoS One 2011, 6 (9), e24341. https://doi.org/10.1371/journal.pone.0024341. (242) Clark, R. S. B.; Kochanek, P. M.; Watkins, S. C.; Chen, M.; Dixon, C. E.; Seidberg, N. A.; Melick, J.; Loeffert, J. E.; Nathaniel, P. D.; Jin, K. L.; et al. Caspase-3 Mediated Neuronal Death after Traumatic Brain Injury in Rats. J. Neurochem. 2000, 74 (2), 740–753. https://doi.org/10.1046/j.1471-4159.2000.740740.x. (243) Knoblach, S. M.; Nikolaeva, M.; Huang, X.; Fan, L.; Krajewski, S.; Reed, J. C.; Faden, A. I. Multiple Caspases Are Activated after Traumatic Brain Injury: Evidence for Involvement in Functional Outcome. J. Neurotrauma 2002, 19 (10), 1155–1170. https://doi.org/10.1089/08977150260337967. (244) Knoblach, S. M.; Alroy, D. A.; Nikolaeva, M.; Cernak, I.; Stoica, B. A.; Faden, A. I. Caspase Inhibitor Z-DEVD-Fmk Attenuates Calpain and Necrotic Cell Death in Vitro and after Traumatic Brain Injury. J. Cereb. Blood Flow Metab. 2004, 24 (10), 1119–1132. https://doi.org/10.1097/01.WCB.0000138664.17682.32. (245) Clark, R. S.; Nathaniel, P. D.; Zhang, X.; Dixon, C. E.; Alber, S. M.; Watkins, S. C.; Melick, J. A.; Kochanek, P. M.; Graham, S. H. Boc-Aspartyl(OMe)-Fluoromethylketone Attenuates Mitochondrial Release of Cytochrome C and Delays Brain Tissue Loss after Traumatic Brain Injury in Rats. J.

Cereb. Blood Flow Metab. 2007, 27 (2), 316–326. https://doi.org/10.1038/sj.jcbfm.9600338. (246) Tomasevic, G.; Raghupathi, R.; Scherbel, U.; Wieloch, T.; McIntosh, T. K. Deletion of the P53 Tumor Suppressor Gene Improves Neuromotor Function but Does Not Attenuate Regional Neuronal Cell Loss Following Experimental Brain Trauma in Mice. J. Neurosci. Res. 2010, 88 (15), 3414–3423. https://doi.org/10.1002/jnr.22491. (247) LaPlaca, M. C.; Zhang, J.; Raghupathi, R.; Li, J. H.; Smith, F.; Bareyre, F. M.; Snyder, S. H.; Graham, D. I.; McIntosh, T. K. Pharmacologic Inhibition of Poly(ADP-Ribose) Polymerase Is Neuroprotective Following Traumatic Brain Injury in Rats. J. Neurotrauma 2001, 18 (4), 369–376. https://doi.org/10.1089/089771501750170912. (248) Slemmer, J. E.; Zhu, C.; Landshamer, S.; Trabold, R.; Grohm, J.; Ardeshiri, A.; Wagner, E.;


Page 54 of 68

Page 55 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Sweeney, M. I.; Blomgren, K.; Culmsee, C.; et al. Causal Role of Apoptosis-Inducing Factor for Neuronal Cell Death Following Traumatic Brain Injury. Am. J. Pathol. 2008, 173 (6), 1795–1805. https://doi.org/10.2353/ajpath.2008.080168. (249) Krajewska, M.; Xu, L.; Xu, W.; Krajewski, S.; Kress, C. L.; Cui, J.; Yang, L.; Irie, F.; Yamaguchi, Y.; Lipton, S. A.; et al. Endoplasmic Reticulum Protein BI-1 Modulates Unfolded Protein Response Signaling and Protects against Stroke and Traumatic Brain Injury. Brain Res. 2011, 1370, 227– 237. https://doi.org/10.1016/j.brainres.2010.11.015. (250) Nakamura, M.; Raghupathi, R.; Merry, D. E.; Scherbel, U.; Saatman, K. E.; McIntosh, T. K. Overexpression of Bcl-2 Is Neuroprotective after Experimental Brain Injury in Transgenic Mice. J.

Comp. Neurol. 1999, 412 (4), 681–692. https://doi.org/10.1002/(SICI)10969861(19991004)412:43.0.CO;2-F. (251) Raghupathi, R.; Fernandez, S. C.; Murai, H.; Trusko, S. P.; Scott, R. W.; Nishioka, W. K.; McIntosh, T. K. BCL-2 Overexpression Attenuates Cortical Cell Loss after Traumatic Brain Injury in Transgenic Mice. J. Cereb. Blood Flow Metab. 1998, 18 (11), 1259–1269. https://doi.org/10.1097/00004647-199811000-00013. (252) Bermpohl, D.; You, Z.; Korsmeyer, S. J.; Moskowitz, M. A.; Whalen, M. J. Traumatic Brain Injury in Mice Deficient in Bid: Effects on Histopathology and Functional Outcome. J. Cereb. Blood Flow

Metab. 2006, 26 (5), 625–633. https://doi.org/10.1038/sj.jcbfm.9600258. (253) Shi, J.; Miles, D. K.; Orr, B. A.; Massa, S. M.; Kernie, S. G. Injury-Induced Neurogenesis in BaxDeficient Mice: Evidence for Regulation by Voltage-Gated Potassium Channels. Eur. J. Neurosci. 2007, 25 (12), 3499–3512. https://doi.org/10.1111/j.1460-9568.2007.05624.x. (254) Sullivan, P. G.; Bruce-Keller, A. J.; Rabchevsky, A. G.; Christakos, S.; Clair, D. K.; Mattson, M. P.; Scheff, S. W. Exacerbation of Damage and Altered NF-KappaB Activation in Mice Lacking Tumor Necrosis Factor Receptors after Traumatic Brain Injury. J. Neurosci. 1999, 19 (0270–6474 SB–IM), 6248–6256. https://doi.org/10.1523/JNEUROSCI.19-15-06248.1999. (255) Schoch, K. M.; Madathil, S. K.; Saatman, K. E. Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury. Neurotherapeutics. Springer-Verlag April 24, 2012, pp 323–337. https://doi.org/10.1007/s13311-012-0107-z. (256) Kim, J. J.; Gean, A. D. Imaging for the Diagnosis and Management of Traumatic Brain Injury.

Neurotherapeutics 2011, 8 (1), 39–53. https://doi.org/10.1007/s13311-010-0003-3. (257) Vink, R. Large Animal Models of Traumatic Brain Injury. J. Neurosci. Res. 2018, 96 (4), 527–535. https://doi.org/10.1002/jnr.24079. (258) Sorby-Adams, A. J.; Vink, R.; Turner, R. J. Large Animal Models of Stroke and Traumatic Brain Injury as Translational Tools. Am. J. Physiol. Integr. Comp. Physiol. 2018, 315 (2), ajpregu.00163.2017. https://doi.org/10.1152/ajpregu.00163.2017. (259) Xiong, Y.; Mahmood, A.; Chopp, M. Animal Models of Traumatic Brain Injury. Nat. Rev. Neurosci. 2013, 14 (2), 128–142. https://doi.org/10.1038/nrn3407.



(260) Cassidy, J. D.; Carroll, L. J.; Peloso, P. M.; Borg, J.; von Holst, H.; Holm, L.; Kraus, J.; Coronado, V. G.; WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. Incidence, Risk Factors and Prevention of Mild Traumatic Brain Injury: Results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J. Rehabil. Med. 2004, No. 43 Suppl, 28–60. https://doi.org/DOI 10.1080/16501960410023732. (261) Kovacs, S. K.; Leonessa, F.; Ling, G. S. F. Blast TBI Models, Neuropathology, and Implications for Seizure Risk. Front. Neurol. 2014, 5, 47. https://doi.org/10.3389/fneur.2014.00047. (262) Milman, A.; Rosenberg, A.; Weizman, R.; Pick, C. G. Mild Traumatic Brain Injury Induces Persistent Cognitive Deficits and Behavioral Disturbances in Mice. J. Neurotrauma 2005, 22 (9), 1003–1010. https://doi.org/10.1089/neu.2005.22.1003. (263) Chen, Y.; Constantini, S.; Trembovler, V.; Weinstock, M.; Shohami, E. An Experimental Model of Closed Head Injury in Mice: Pathophysiology, Histopathology, and Cognitive Deficits. J.

Neurotrauma 1996, 13 (10), 557–568. https://doi.org/10.1089/neu.1996.13.557. (264) Baratz, R.; Tweedie, D.; Rubovitch, V.; Luo, W.; Yoon, J. S.; Hoffer, B. J.; Greig, N. H.; Pick, C. G. Tumor Necrosis Factor-α Synthesis Inhibitor, 3,6′- Dithiothalidomide, Reverses Behavioral Impairments Induced by Minimal Traumatic Brain Injury in Mice. J. Neurochem. 2011, 118 (6), 1032–1042. https://doi.org/10.1111/j.1471-4159.2011.07377.x. (265) Baratz, R.; Tweedie, D.; Wang, J. Y.; Rubovitch, V.; Luo, W.; Hoffer, B. J.; Greig, N. H.; Pick, C. G. Transiently Lowering Tumor Necrosis Factor-Aα Synthesis Ameliorates Neuronal Cell Loss and Cognitive Impairments Induced by Minimal Traumatic Brain Injury in Mice. J. Neuroinflammation 2015, 12 (1), 45. https://doi.org/10.1186/s12974-015-0237-4. (266) Tweedie, D.; Rachmany, L.; Rubovitch, V.; Zhang, Y.; Becker, K. G.; Perez, E.; Hoffer, B. J.; Pick, C. G.; Greig, N. H. Changes in Mouse Cognition and Hippocampal Gene Expression Observed in a Mild Physical- and Blast-Traumatic Brain Injury. Neurobiol. Dis. 2013, 54, 1–11. https://doi.org/10.1016/j.nbd.2013.02.006. (267) Fann, J. R.; Hart, T.; Schomer, K. G. Treatment for Depression after Traumatic Brain Injury: A Systematic Review. J. Neurotrauma 2009, 26 (12), 2383–2402. https://doi.org/10.1089/neu.2009.1091. (268) Chhor, V.; Moretti, R.; Le Charpentier, T.; Sigaut, S.; Lebon, S.; Schwendimann, L.; Oré, M.-V.; Zuiani, C.; Milan, V.; Josserand, J.; et al. Role of Microglia in a Mouse Model of Paediatric Traumatic Brain Injury. Brain. Behav. Immun. 2017, 63, 197–209. (269) Homsi, S.; Piaggio, T.; Croci, N.; Noble, F.; Plotkine, M.; Marchand-Leroux, C.; Jafarian-Tehrani, M. Blockade of Acute Microglial Activation by Minocycline Promotes Neuroprotection and Reduces Locomotor Hyperactivity after Closed Head Injury in Mice: A Twelve-Week Follow-Up Study. J.

Neurotrauma 2010, 27 (5), 911–921. https://doi.org/10.1089/neu.2009.1223. (270) Bye, N.; Habgood, M. D.; Callaway, J. K.; Malakooti, N.; Potter, A.; Kossmann, T.; MorgantiKossmann, M. C. Transient Neuroprotection by Minocycline Following Traumatic Brain Injury Is


Page 56 of 68

Page 57 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Associated with Attenuated Microglial Activation but No Changes in Cell Apoptosis or Neutrophil Infiltration. Exp. Neurol. 2007, 204 (1), 220–233. https://doi.org/10.1016/j.expneurol.2006.10.013. (271) Singh, K.; Trivedi, R.; Devi, M. M.; Tripathi, R. P.; Khushu, S. Longitudinal Changes in the DTI Measures, Anti-GFAP Expression and Levels of Serum Inflammatory Cytokines Following Mild Traumatic Brain Injury. Exp. Neurol. 2016, 275, 427–435. https://doi.org/10.1016/j.expneurol.2015.07.016. (272) Kane, M. J.; Pérez, M. A.; Briggs, D. I.; Viano, D. C.; Kreipke, C. W.; Kuhn, D. M.; Dingell, J. D. A Mouse Model of Human Repetitive Mild Traumatic Brain Injury. J Neurosci Methods J Neurosci

Methods. January 2012, 15 (2031), 41–49. https://doi.org/10.1016/j.jneumeth.2011.09.003.A. (273) Shohami, E.; Gallily, R.; Mechoulam, R.; Bass, R.; Ben-Hur, T. Cytokine Production in the Brain Following Closed Head Injury: Dexanabinol (HU-211) Is a Novel TNF-α Inhibitor and an Effective Neuroprotectant. J. Neuroimmunol. 1997, 72 (2), 169–177. https://doi.org/10.1016/S01655728(96)00181-6. (274) Shohami, E.; Novikov, M.; Bass, R.; Yamin, A.; Gallily, R. Closed Head Injury Triggers Early Production of TNFα and IL-6 by Brain Tissue. J. Cereb. Blood Flow Metab. 1994, 14 (4), 615–619. https://doi.org/10.1038/jcbfm.1994.76. (275) Tweedie, D.; Rachmany, L.; Rubovitch, V.; Lehrmann, E.; Zhang, Y.; Becker, K. G.; Perez, E.; Miller, J.; Hoffer, B. J.; Greig, N. H.; et al. Exendin-4, a Glucagon-like Peptide-1 Receptor Agonist Prevents MTBI-Induced Changes in Hippocampus Gene Expression and Memory Deficits in Mice.

Exp. Neurol. 2013, 239 (1), 170–182. https://doi.org/10.1016/j.expneurol.2012.10.001. (276) Tweedie, D.; Milman, A.; Holloway, H. W.; Li, Y.; Harvey, B. K.; Shen, H.; Pistell, P. J.; Lahiri, D. K.; Hoffer, B. J.; Wang, Y.; et al. Apoptotic and Behavioral Sequelae of Mild Brain Trauma in Mice.

J. Neurosci. Res. 2007, 85 (4), 805–815. https://doi.org/10.1002/jnr.21160. (277) Schwarzbold, M. L.; Rial, D.; De Bem, T.; Machado, D. G.; Cunha, M. P.; dos Santos, A. A.; dos Santos, D. B.; Figueiredo, C. P.; Farina, M.; Goldfeder, E. M.; et al. Effects of Traumatic Brain Injury of Different Severities on Emotional, Cognitive, and Oxidative Stress-Related Parameters in Mice. J. Neurotrauma 2010, 27 (10), 1883–1893. https://doi.org/10.1089/neu.2010.1318. (278) Lai, J.-H.; Karlsson, T. E.; Wu, J. C.-C.; Huang, C.-Z.; Chen, Y.-H.; Kang, S.-J.; Brodin, A. T. S.; Hoffer, B. J.; Olson, L.; Chiang, Y.-H.; et al. Role of Nogo Receptor-1 for Recovery of Balance, Cognition, and Emotion after Mild Traumatic Brain Injury in Mice. J. Neurotrauma 2018, neu.2018.5949. https://doi.org/10.1089/neu.2018.5949. (279) Tashlykov, V.; Katz, Y.; Volkov, A.; Gazit, V.; Schreiber, S.; Zohar, O.; Pick, C. G. Minimal Traumatic Brain Injury Induce Apoptotic Cell Death in Mice. J. Mol. Neurosci. 2009, 37 (1), 16–24. https://doi.org/10.1007/s12031-008-9094-2. (280) Tashlykov, V.; Katz, Y.; Gazit, V.; Zohar, O.; Schreiber, S.; Pick, C. G. Apoptotic Changes in the Cortex and Hippocampus Following Minimal Brain Trauma in Mice. Brain Res. 2007, 1130 (1), 197–205. https://doi.org/10.1016/j.brainres.2006.10.032.



(281) Yaka, R.; Biegon, A.; Grigoriadis, N.; Simeonidou, C.; Grigoriadis, S.; Alexandrovich, A. G.; Matzner, H.; Schumann, J.; Trembovler, V.; Tsenter, J.; et al. D-Cycloserine Improves Functional Recovery and Reinstates Long-Term Potentiation (LTP) in a Mouse Model of Closed Head Injury.

FASEB J. 2007, 21 (9), 2033–2041. https://doi.org/10.1096/fj.06-7856com. (282) Shimon, M. Ben; Zeimer, T.; Stein, E. S.; Artan-Furman, A.; Harnof, S.; Chapman, J.; Eisenkraft, A.; Pick, C. G.; Maggio, N. Recovery from Trauma Induced Amnesia Correlates with Normalization of Thrombin Activity in the Mouse Hippocampus. PLoS One 2017, 12 (11), e0188524. https://doi.org/10.1371/journal.pone.0188524. (283) Esen, F.; Erdem, T.; Aktan, D.; Kalayci, R.; Cakar, N.; Kaya, M.; Telci, L. Effects of Magnesium Administration on Brain Edema and Blood-Brain Barrier Breakdown after Experimental Traumatic Brain Injury in Rats. J. Neurosurg. Anesthesiol. 2003, 15 (2), 119–125. https://doi.org/10.1097/00008506-200304000-00009. (284) Habgood, M. D.; Bye, N.; Dziegielewska, K. M.; Ek, C. J.; Lane, M. A.; Potter, A.; MorgantiKossmann, C.; Saunders, N. R. Changes in Blood-Brain Barrier Permeability to Large and Small Molecules Following Traumatic Brain Injury in Mice. Eur. J. Neurosci. 2007, 25 (1), 231–238. https://doi.org/10.1111/j.1460-9568.2006.05275.x. (285) Fanne, R. A.; Nassar, T.; Mazuz, A.; Waked, O.; Heyman, S. N.; Hijazi, N.; Goelman, G.; Higazi, A. A.-R. Neuroprotection by Glucagon: Role of Gluconeogenesis. J. Neurosurg. 2011, 114 (1), 85– 91. https://doi.org/10.3171/2010.4.JNS10263. (286) Kuehn, R.; Simard, P. F.; Driscoll, I.; Keledjian, K.; Ivanova, S.; Tosun, C.; Williams, A.; Bochicchio, G.; Gerzanich, V.; Simard, J. M. Rodent Model of Direct Cranial Blast Injury. J.

Neurotrauma 2011, 28 (10), 2155–2169. https://doi.org/10.1089/neu.2010.1532. (287) Readnower, R. D.; Chavko, M.; Adeeb, S.; Conroy, M. D.; Pauly, J. R.; McCarron, R. M.; Sullivan, P. G. Increase in Blood-Brain Barrier Permeability, Oxidative Stress, and Activated Microglia in a Rat Model of Blast-Induced Traumatic Brain Injury. J. Neurosci. Res. 2010, 88 (16), 3530–3539. https://doi.org/10.1002/jnr.22510. (288) Svetlov, S. I.; Prima, V.; Kirk, D. R.; Gutierrez, H.; Curley, K. C.; Hayes, R. L.; Wang, K. K. W. Morphologic and Biochemical Characterization of Brain Injury in a Model of Controlled Blast Overpressure Exposure. J. Trauma - Inj. Infect. Crit. Care 2010, 69 (4), 795–804. https://doi.org/10.1097/TA.0b013e3181bbd885. (289) Sajja, V. S. S. S.; Galloway, M.; Ghoddoussi, F.; Kepsel, A.; Vandevord, P. Effects of BlastInduced Neurotrauma on the Nucleus Accumbens. J. Neurosci. Res. 2013, 91 (4), 593–601. https://doi.org/10.1002/jnr.23179. (290) Du, X.; Ewert, D. L.; Cheng, W.; West, M. B.; Lu, J.; Li, W.; Floyd, R. A.; Kopke, R. D. Effects of Antioxidant Treatment on Blast-Induced Brain Injury. PLoS One 2013, 8 (11), e80138. https://doi.org/10.1371/journal.pone.0080138. (291) Säljö, A.; Bao, F.; Hamberger, A.; Haglid, K. G.; Hansson, H. A. Exposure to Short-Lasting


Page 58 of 68

Page 59 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Impulse Noise Causes Microglial and Astroglial Cell Activation in the Adult Rat Brain.

Pathophysiology 2001, 8 (2), 105–111. https://doi.org/10.1016/S0928-4680(01)00067-0. (292) Sajja, V. S. S. S.; Ereifej, E. S.; VandeVord, P. J. Hippocampal Vulnerability and Subacute Response Following Varied Blast Magnitudes. Neurosci. Lett. 2014, 570, 33–37. https://doi.org/10.1016/J.NEULET.2014.03.072. (293) Cho, H. J.; Sajja, V. S. S. S.; VandeVord, P. J.; Lee, Y. W. Blast Induces Oxidative Stress, Inflammation, Neuronal Loss and Subsequent Short-Term Memory Impairment in Rats.

Neuroscience 2013, 253, 9–20. https://doi.org/10.1016/J.NEUROSCIENCE.2013.08.037. (294) Kochanek, P. M.; Dixon, C. E.; Shellington, D. K.; Shin, S. S.; Bayır, H.; Jackson, E. K.; Kagan, V. E.; Yan, H. Q.; Swauger, P. V; Parks, S. A.; et al. Screening of Biochemical and Molecular Mechanisms of Secondary Injury and Repair in the Brain after Experimental Blast-Induced Traumatic Brain Injury in Rats. J. Neurotrauma 2013, 30 (11), 920–937. https://doi.org/10.1089/neu.2013.2862. (295) Heim, L. R.; Bader, M.; Edut, S.; Rachmany, L.; Baratz-Goldstein, R.; Lin, R.; Elpaz, A.; Qubty, D.; Bikovski, L.; Rubovitch, V.; et al. The Invisibility of Mild Traumatic Brain Injury: Impaired Cognitive Performance as a Silent Symptom. J. Neurotrauma 2017, 34 (17). https://doi.org/10.1089/neu.2016.4909. (296) Abdul-Muneer, P. M.; Schuetz, H.; Wang, F.; Skotak, M.; Jones, J.; Gorantla, S.; Zimmerman, M. C.; Chandra, N.; Haorah, J. Induction of Oxidative and Nitrosative Damage Leads to Cerebrovascular Inflammation in an Animal Model of Mild Traumatic Brain Injury Induced by Primary Blast. Free Radic. Biol. Med. 2013, 60, 282–291. https://doi.org/10.1016/j.freeradbiomed.2013.02.029. (297) Vogel, E. W.; Effgen, G. B.; Patel, T. P.; Meaney, D. F.; Bass, C. R. D.; Morrison, B. Isolated Primary Blast Inhibits Long-Term Potentiation in Organotypic Hippocampal Slice Cultures. J.

Neurotrauma 2016, 33 (7), 652–661. https://doi.org/10.1089/neu.2015.4045. (298) Goldstein, L. E.; Fisher, A. M.; Tagge, C. A.; Zhang, X.-L.; Velisek, L.; Sullivan, J. A.; Upreti, C.; Kracht, J. M.; Ericsson, M.; Wojnarowicz, M. W.; et al. Chronic Traumatic Encephalopathy in BlastExposed Military Veterans and a Blast Neurotrauma Mouse Model. Sci. Transl. Med. 2012, 4 (134). https://doi.org/10.1126/scitranslmed.3003716. (299) Chio, C. C.; Chang, C. H.; Wang, C. C.; Cheong, C. U.; Chao, C. M.; Cheng, B. C.; Yang, C. Z.; Chang, C. P. Etanercept Attenuates Traumatic Brain Injury in Rats by Reducing Early Microglial Expression of Tumor Necrosis Factor-α. BMC Neurosci. 2013, 14 (1), 33. https://doi.org/10.1186/1471-2202-14-33. (300) Cao, T.; Thomas, T. C.; Ziebell, J. M.; Pauly, J. R.; Lifshitz, J. Morphological and Genetic Activation of Microglia after Diffuse Traumatic Brain Injury in the Rat. Neuroscience 2012, 225, 65– 75. https://doi.org/10.1016/j.neuroscience.2012.08.058. (301) Shojo, H.; Borlongan, C. V.; Mabuchi, T. Genetic and Histological Alterations Reveal Key Role of



Prostaglandin Synthase and Cyclooxygenase 1 and 2 in Traumatic Brain Injury–Induced Neuroinflammation in the Cerebral Cortex of Rats Exposed to Moderate Fluid Percussion Injury.

Cell Transplant. 2017, 26 (7), 1301–1313. https://doi.org/10.1177/0963689717715169. (302) Gao, W.; Zhao, Z.; Yu, G.; Zhou, Z.; Zhou, Y.; Hu, T.; Jiang, R.; Zhang, J. VEGI Attenuates the Inflammatory Injury and Disruption of Blood-Brain Barrier Partly by Suppressing the TLR4/NF-ΚB Signaling Pathway in Experimental Traumatic Brain Injury. Brain Res. 2015, 1622, 230–239. https://doi.org/10.1016/j.brainres.2015.04.035. (303) Webster, K. M.; Wright, D. K.; Sun, M.; Semple, B. D.; Ozturk, E.; Stein, D. G.; O’Brien, T. J.; Shultz, S. R. Progesterone Treatment Reduces Neuroinflammation, Oxidative Stress and Brain Damage and Improves Long-Term Outcomes in a Rat Model of Repeated Mild Traumatic Brain Injury. J. Neuroinflammation 2015, 12 (1), 238. https://doi.org/10.1186/s12974-015-0457-7. (304) Fan, L.; Young, P. R.; Barone, F. C.; Feuerstein, G. Z.; Smith, D. H.; McIntosh, T. K. Experimental Brain Injury Induces Differential Expression of Tumor Necrosis Factor-α MRNA in the CNS. Mol.

Brain Res. 1996, 36 (2), 287–291. https://doi.org/10.1016/0169-328X(95)00274-V. (305) Muccigrosso, M. M.; Ford, J.; Benner, B.; Moussa, D.; Burnsides, C.; Fenn, A. M.; Popovich, P. G.; Lifshitz, J.; Walker, F. R.; Eiferman, D. S.; et al. Cognitive Deficits Develop 1 Month after Diffuse Brain Injury and Are Exaggerated by Microglia-Associated Reactivity to Peripheral Immune Challenge. Brain. Behav. Immun. 2016, 54, 95–109. https://doi.org/10.1016/J.BBI.2016.01.009. (306) Spain, A.; Daumas, S.; Lifshitz, J.; Rhodes, J.; Andrews, P. J. D.; Horsburgh, K.; Fowler, J. H. Mild Fluid Percussion Injury in Mice Produces Evolving Selective Axonal Pathology and Cognitive Deficits Relevant to Human Brain Injury. J. Neurotrauma 2010, 27 (8), 1429–1438. https://doi.org/10.1089/neu.2010.1288. (307) Rink, A.; Fung, K. M.; Trojanowski, J. Q.; Lee, V. M.; Neugebauer, E.; McIntosh, T. K. Evidence of Apoptotic Cell Death after Experimental Traumatic Brain Injury in the Rat. Am. J. Pathol. 1995,

147 (6), 1575–1583. (308) Van Bregt, D. R.; Thomas, T. C.; Hinzman, J. M.; Cao, T.; Liu, M.; Bing, G.; Gerhardt, G. A.; Pauly, J. R.; Lifshitz, J. Substantia Nigra Vulnerability after a Single Moderate Diffuse Brain Injury in the Rat. Exp. Neurol. 2012, 234 (1), 8–19. https://doi.org/10.1016/j.expneurol.2011.12.003. (309) Karklin Fontana, A. C.; Fox, D. P.; Zoubroulis, A.; Valente Mortensen, O.; Raghupathi, R. Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-Methyl-1-Nicotinoyl-2Pyrazoline (MS-153) Following Traumatic Brain Injury in the Adult Rat. J. Neurotrauma 2016, 33 (11), 1073–1083. https://doi.org/10.1089/neu.2015.4079. (310) Sanders, M. J.; Sick, T. J.; Perez-Pinzon, M. A.; Dietrich, W. D.; Green, E. J. Chronic Failure in the Maintenance of Long-Term Potentiation Following Fluid Percussion Injury in the Rat. Brain Res. 2000, 861 (1), 69–76. https://doi.org/10.1016/S0006-8993(00)01986-7. (311) Chen, Y.-H.; Kuo, T.-T.; Yi-Kung Huang, E.; Hoffer, B. J.; Chou, Y.-C.; Chiang, Y.-H.; Ma, H.-I.; Miller, J. P. Profound Deficits in Hippocampal Synaptic Plasticity after Traumatic Brain Injury and


Page 60 of 68

Page 61 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Seizure Is Ameliorated by Prophylactic Levetiracetam. Oncotarget 2018, 9 (14), 11515–11527. https://doi.org/10.18632/oncotarget.23923. (312) Wu, A.; Ying, Z.; Gomez-Pinilla, F. Dietary Curcumin Counteracts the Outcome of Traumatic Brain Injury on Oxidative Stress, Synaptic Plasticity, and Cognition. Exp. Neurol. 2006, 197 (2), 309– 317. https://doi.org/10.1016/J.EXPNEUROL.2005.09.004. (313) Tomura, S.; Nawashiro, H.; Otani, N.; Uozumi, Y.; Toyooka, T.; Ohsumi, A.; Shima, K. Effect of Decompressive Craniectomy on Aquaporin-4 Expression after Lateral Fluid Percussion Injury in Rats. J. Neurotrauma 2011, 28 (2), 237–243. https://doi.org/10.1089/neu.2010.1443. (314) Lima, F. D.; Oliveira, M. S.; Furian, A. F.; Souza, M. A.; Rambo, L. M.; Ribeiro, L. R.; Silva, L. F. A.; Retamoso, L. T.; Hoffmann, M. S.; Magni, D. V.; et al. Adaptation to Oxidative Challenge Induced by Chronic Physical Exercise Prevents Na+,K+-ATPase Activity Inhibition after Traumatic Brain Injury. Brain Res. 2009, 1279, 147–155. https://doi.org/10.1016/J.BRAINRES.2009.04.052. (315) Hinzman, J. M.; Thomas, T. C.; Burmeister, J. J.; Quintero, J. E.; Huettl, P.; Pomerleau, F.; Gerhardt, G. A.; Lifshitz, J. Diffuse Brain Injury Elevates Tonic Glutamate Levels and PotassiumEvoked Glutamate Release in Discrete Brain Regions at Two Days Post-Injury: An Enzyme-Based Microelectrode Array Study. J. Neurotrauma 2010, 27 (5), 889–899. https://doi.org/10.1089/neu.2009.1238. (316) Sun, F. Y.; Faden, A. I. Pretreatment with Antisense Oligodeoxynucleotides Directed against the NMDA-R1 Receptor Enhances Survival and Behavioral Recovery Following Traumatic Brain Injury in Rats. Brain Res. 1995, 693 (1–2), 163–168. https://doi.org/10.1016/0006-8993(95)00731-5. (317) Okiyama, K.; Smith, D. H.; Gennarelli, T. A.; Simon, R. P.; Leach, M.; McIntosh, T. K. The Sodium Channel Blocker and Glutamate Release Inhibitor BW1003C87 and Magnesium Attenuate Regional Cerebral Edema Following Experimental Brain Injury in the Rat. J. Neurochem. 1995, 64 (2), 802–809. https://doi.org/10.1046/j.1471-4159.1995.64020802.x. (318) Matsushita, Y.; Shima, K.; Nawashiro, H.; Wada, K. Real-Time Monitoring of Glutamate Following Fluid Percussion Brain Injury With Hypoxia in the Rat. J. Neurotrauma 2000, 17 (2), 143–153. https://doi.org/10.1089/neu.2000.17.143. (319) Shitaka, Y.; Tran, H. T.; Bennett, R. E.; Sanchez, L.; Levy, M. A.; Dikranian, K.; Brody, D. L. Repetitive Closed-Skull Traumatic Brain Injury in Mice Causes Persistent Multifocal Axonal Injury and Microglial Reactivity. J. Neuropathol. Exp. Neurol. 2011, 70 (7), 551–567. https://doi.org/10.1097/NEN.0b013e31821f891f. (320) Sandhir, R.; Onyszchuk, G.; Berman, N. E. J. Exacerbated Glial Response in the Aged Mouse Hippocampus Following Controlled Cortical Impact Injury. Exp. Neurol. 2008, 213 (2), 372–380. https://doi.org/10.1016/j.expneurol.2008.06.013. (321) Zhang, Q.-G.; Laird, M. D.; Han, D.; Nguyen, K.; Scott, E.; Dong, Y.; Dhandapani, K. M.; Brann, D. W. Critical Role of NADPH Oxidase in Neuronal Oxidative Damage and Microglia Activation Following Traumatic Brain Injury. PLoS One 2012, 7 (4), e34504.



https://doi.org/10.1371/journal.pone.0034504. (322) Turtzo, L. C.; Lescher, J.; Janes, L.; Dean, D. D.; Budde, M. D.; Frank, J. A. Macrophagic and Microglial Responses after Focal Traumatic Brain Injury in the Female Rat. J. Neuroinflammation 2014, 11, 82. https://doi.org/10.1186/1742-2094-11-82. (323) Isaksson, J.; Hillered, L.; Olsson, Y. Cognitive and Histopathological Outcome after Weight-Drop Brain Injury in the Rat: Influence of Systemic Administration of Monoclonal Antibodies to ICAM-1.

Acta Neuropathol. 2001, 102 (3), 246–256. https://doi.org/10.1007/s004010100361. (324) Batsaikhan, B.; Wang, J.-Y.; Scerba, M.; Tweedie, D.; Greig, N.; Miller, J.; Hoffer, B.; Lin, C.-T.; Wang, J.-Y.; Batsaikhan, B.; et al. Post-Injury Neuroprotective Effects of the Thalidomide Analog 3,6′-Dithiothalidomide on Traumatic Brain Injury. Int. J. Mol. Sci. 2019, 20 (3), 502. https://doi.org/10.3390/ijms20030502. (325) He, J.; Evans, C.-O.; Hoffman, S. W.; Oyesiku, N. M.; Stein, D. G. Progesterone and Allopregnanolone Reduce Inflammatory Cytokines after Traumatic Brain Injury. Exp. Neurol. 2004,

189 (2), 404–412. https://doi.org/10.1016/J.EXPNEUROL.2004.06.008. (326) Choi, B. Y.; Jang, B. G.; Kim, J. H.; Lee, B. E.; Sohn, M.; Song, H. K.; Suh, S. W. Prevention of Traumatic Brain Injury-Induced Neuronal Death by Inhibition of NADPH Oxidase Activation. Brain

Res. 2012, 1481, 49–58. https://doi.org/10.1016/j.brainres.2012.08.032. (327) Ansari, M. A.; Roberts, K. N.; Scheff, S. W. Oxidative Stress and Modification of Synaptic Proteins in Hippocampus after Traumatic Brain Injury. Free Radic. Biol. Med. 2008, 45 (4), 443–452. https://doi.org/10.1016/j.freeradbiomed.2008.04.038. (328) Albensi, B. C.; Sullivan, P. G.; Thompson, M. B.; Scheff, S. W.; Mattson, M. P. Cyclosporin Ameliorates Traumatic Brain-Injury-Induced Alterations of Hippocampal Synaptic Plasticity. Exp.

Neurol. 2000, 162 (2), 385–389. https://doi.org/10.1006/exnr.1999.7338. (329) Başkaya, M. K.; Rao, A. M.; Doǧan, A.; Donaldson, D.; Dempsey, R. J. The Biphasic Opening of the Blood-Brain Barrier in the Cortex and Hippocampus after Traumatic Brain Injury in Rats.

Neurosci. Lett. 1997, 226 (1), 33–36. https://doi.org/10.1021/bp050379z. (330) Lopez, N. E.; Krzyzaniak, M. J.; Blow, C.; Putnam, J.; Ortiz-Pomales, Y.; Hageny, A.-M.; Eliceiri, B.; Coimbra, R.; Bansal, V. Ghrelin Prevents Disruption of the Blood–Brain Barrier after Traumatic Brain Injury. J. Neurotrauma 2012, 29 (2), 385–393. https://doi.org/10.1089/neu.2011.2053. (331) Marklund, N.; Clausen, F.; Lewander, T.; Hillered, L. Monitoring of Reactive Oxygen Species Production after Traumatic Brain Injury in Rats with Microdialysis and the 4-Hydroxybenzoic Acid Trapping Method. J. Neurotrauma 2001, 18 (11), 1217–1227. https://doi.org/10.1089/089771501317095250. (332) Nilsson, P.; Hillered, L.; Ponten, U.; Ungerstedt, U. Changes in Cortical Extracellular Levels of Energy-Related Metabolites and Amino Acids Following Concussive Brain Injury in Rats. J. Cereb.

Blood Flow Metab. 1990, 10 (5), 631–637. https://doi.org/10.1038/jcbfm.1990.115. (333) Rose, M. E.; Huerbin, M. B.; Melick, J.; Marion, D. W.; Palmer, A. M.; Schiding, J. K.; Kochanek,


Page 62 of 68

Page 63 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


P. M.; Graham, S. H. Regulation of Interstitial Excitatory Amino Acid Concentrations after Cortical Contusion Injury. Brain Res. 2002, 943 (1), 15–22. https://doi.org/10.1016/S0006-8993(02)024459. (334) Rao, V. L. R.; Dogan, A.; Bowen, K. K.; Todd, K. G.; Dempsey, R. J. Antisense Knockdown of the Glial Glutamate Transporter GLT-1 Exacerbates Hippocampal Neuronal Damage Following Traumatic Injury to Rat Brain. Eur. J. Neurosci. 2001, 13 (1), 119–128. https://doi.org/10.1046/j.1460-9568.2001.01367.x. (335) Seino, Y.; Fukushima, M.; Yabe, D. GIP and GLP-1, the Two Incretin Hormones: Similarities and Differences. J. Diabetes Investig. 2010, 1 (1–2), 8–23. https://doi.org/10.1111/j.20401124.2010.00022.x. (336) Holst, J. J.; Ørskov, C.; Vagn Nielsen, O.; Schwartz, T. W. Truncated Glucagon-like Peptide I, an Insulin-Releasing Hormone from the Distal Gut. FEBS Lett. 1987, 211 (2), 169–174. https://doi.org/10.1016/0014-5793(87)81430-8. (337) Graaf, C. de; Donnelly, D.; Wootten, D.; Lau, J.; Sexton, P. M.; Miller, L. J.; Ahn, J.-M.; Liao, J.; Fletcher, M. M.; Yang, D.; et al. Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes. Pharmacol. Rev. 2016, 68 (4), 954–1013. https://doi.org/10.1124/pr.115.011395. (338) Lee, Y. H.; Wang, M.-Y.; Yu, X.-X.; Unger, R. H. Glucagon Is the Key Factor in the Development of Diabetes. Diabetologia 2016, 59 (7), 1372–1375. https://doi.org/10.1007/s00125-016-3965-9. (339) Abraham, M. A.; Lam, T. K. T. Glucagon Action in the Brain. Diabetologia. Springer Berlin Heidelberg July 26, 2016, pp 1367–1371. https://doi.org/10.1007/s00125-016-3950-3. (340) Campos, R. V; Lee, Y. C.; Drucker, D. J. Divergent Tissue-Specific and Developmental Expression of Receptors for Glucagon and Glucagon-like Peptide-1 in the Mouse. Endocrinology 1994, 134 (5), 2156–2164. https://doi.org/10.1210/endo.134.5.8156917. (341) Nyberg, J.; Anderson, M. F.; Meister, B.; Alborn, A.-M.; Ström, A.-K.; Brederlau, A.; Illerskog, A.C.; Nilsson, O.; Kieffer, T. J.; Hietala, M. A.; et al. Glucose-Dependent Insulinotropic Polypeptide Is Expressed in Adult Hippocampus and Induces Progenitor Cell Proliferation. J. Neurosci. 2005, 25 (7), 1816–1825. https://doi.org/10.1523/JNEUROSCI.4920-04.2005. (342) Zhang, Y.; Chen, K.; Sloan, S. A.; Bennett, M. L.; Scholze, A. R.; O’Keeffe, S.; Phatnani, H. P.; Guarnieri, P.; Caneda, C.; Ruderisch, N.; et al. An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex. J. Neurosci. 2014, 34 (36), 11929–11947. https://doi.org/10.1523/JNEUROSCI.1860-14.2014. (343) Heppner, K. M.; Kirigiti, M.; Secher, A.; Paulsen, S. J.; Buckingham, R.; Pyke, C.; Knudsen, L. B.; Vrang, N.; Grove, K. L. Expression and Distribution of Glucagon-like Peptide-1 Receptor MRNA, Protein and Binding in the Male Nonhuman Primate (Macaca Mulatta) Brain. Endocrinology 2015,

156 (1), 255–267. https://doi.org/10.1210/en.2014-1675. (344) Richards, P.; Parker, H. E.; Adriaenssens, A. E.; Hodgson, J. M.; Cork, S. C.; Trapp, S.; Gribble,



F. M.; Reimann, F. Identification and Characterization of GLP-1 Receptor-Expressing Cells Using a New Transgenic Mouse Model. Diabetes 2014, 63 (4), 1224–1233. https://doi.org/10.2337/db131440. (345) Chowen, J. A.; Fonseca, F. R. De; Alvarez, E.; Navarro, M.; García-Segura, L. M.; Blázquez, E. Increased Glucagon-like Peptide-1 Receptor Expression in Glia after Mechanical Lesion of the Rat Brain. Neuropeptides 1999, 33 (3), 212–215. https://doi.org/10.1054/npep.1999.0757. (346) Jazayeri, A.; Rappas, M.; Brown, A. J. H.; Kean, J.; Errey, J. C.; Robertson, N. J.; Fiez-Vandal, C.; Andrews, S. P.; Congreve, M.; Bortolato, A.; et al. Crystal Structure of the GLP-1 Receptor Bound to a Peptide Agonist. Nature 2017, 546 (7657), 254–258. https://doi.org/10.1038/nature22800. (347) Koole, C.; Wootten, D.; Simms, J.; Miller, L. J.; Christopoulos, A.; Sexton, P. M. Second Extracellular Loop of Human Glucagon-like Peptide-1 Receptor (GLP-1R) Has a Critical Role in GLP-1 Peptide Binding and Receptor Activation. J. Biol. Chem. 2012, 287 (6), 3642–3658. https://doi.org/10.1074/jbc.M111.309328. (348) Lei, S.; Clydesdale, L.; Dai, A.; Cai, X.; Feng, Y.; Yang, D.; Liang, Y. L.; Koole, C.; Zhao, P.; Coudrat, T.; et al. Two Distinct Domains of the Glucagon-like Peptide-1 Receptor Control PeptideMediated Biased Agonism. J. Biol. Chem. 2018, 293 (24), 9370–9387. https://doi.org/10.1074/jbc.RA118.003278. (349) Wootten, D.; Reynolds, C. A.; Smith, K. J.; Mobarec, J. C.; Koole, C.; Savage, E. E.; Pabreja, K.; Simms, J.; Sridhar, R.; Furness, S. G. B.; et al. The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism. Cell 2016, 165 (7), 1632–1643. https://doi.org/10.1016/j.cell.2016.05.023. (350) Yin, Y.; Zhou, X. E.; Hou, L.; Zhao, L. H.; Liu, B.; Wang, G.; Jiang, Y.; Melcher, K.; Xu, H. E. An Intrinsic Agonist Mechanism for Activation of Glucagon-like Peptide-1 Receptor by Its Extracellular Domain. Cell Discov. 2016, 2 (1), 16042. https://doi.org/10.1038/celldisc.2016.42. (351) Tengholm, A.; Gylfe, E. CAMP Signalling in Insulin and Glucagon Secretion. Diabetes, Obes.

Metab. 2017, 19, 42–53. https://doi.org/10.1111/dom.12993. (352) Li, Y.; Tweedie, D.; Mattson, M. P.; Holloway, H. W.; Greig, N. H. Enhancing the GLP-1 Receptor Signaling Pathway Leads to Proliferation and Neuroprotection in Human Neuroblastoma Cells. J.

Neurochem. 2010, 113 (6), 1621–1631. https://doi.org/10.1111/j.1471-4159.2010.06731.x. (353) Mangmool, S.; Hemplueksa, P.; Parichatikanond, W.; Chattipakorn, N. Epac Is Required for GLP1R-Mediated Inhibition of Oxidative Stress and Apoptosis in Cardiomyocytes. Mol. Endocrinol. 2015, 29 (4), 583–596. https://doi.org/10.1210/me.2014-1346. (354) Roscioni, S. S.; Elzinga, C. R. S.; Schmidt, M. Epac: Effectors and Biological Functions. In

Naunyn-Schmiedeberg’s Archives of Pharmacology; Springer-Verlag, 2008; Vol. 377, pp 345–357. https://doi.org/10.1007/s00210-007-0246-7. (355) Rowlands, J.; Heng, J.; Newsholme, P.; Carlessi, R. Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function. Front. Endocrinol. (Lausanne). 2018, 9 (November), 1–


Page 64 of 68

Page 65 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


23. https://doi.org/10.3389/fendo.2018.00672. (356) Parker, D.; Montminy, M. R. Phosphorylation of CREB at Ser-133 Induces Complex Formation with CREB-Binding Protein via a Direct Mechanism. Mol. Cell. Biol. 1996, 16 (2), 694–703. https://doi.org/10.1210/jc.2005-1380. (357) Ehrlich, D. E.; Josselyn, S. A. Plasticity-Related Genes in Brain Development and AmygdalaDependent Learning. Genes, Brain and Behavior. January 2016, pp 125–143. https://doi.org/10.1111/gbb.12255. (358) Yang, Y.; Choi, P. P.; Smith, W. W.; Xu, W.; Ma, D.; Cordner, Z. A.; Liang, N. C.; Moran, T. H. Exendin-4 Reduces Food Intake via the PI3K/AKT Signaling Pathway in the Hypothalamus. Sci.

Rep. 2017, 7 (1), 6936. https://doi.org/10.1038/s41598-017-06951-0. (359) Downward, J. PI 3-Kinase, Akt and Cell Survival. Seminars in Cell and Developmental Biology. Academic Press April 1, 2004, pp 177–182. https://doi.org/10.1016/j.semcdb.2004.01.002. (360) Athauda, D.; Foltynie, T. The Glucagon-like Peptide 1 (GLP) Receptor as a Therapeutic Target in Parkinson’s Disease: Mechanisms of Action. Drug Discov. Today 2016, 21 (5), 802–818. https://doi.org/10.1016/j.drudis.2016.01.013. (361) Pugazhenthit, S.; Nesterova, A.; Sable, C.; Heidenreich, K. A.; Boxer, L. M.; Heasley, L. E.; Reusch, J. E. B. Akt/Protein Kinase B up-Regulates Bcl-2 Expression through CAMP-Response Element-Binding Protein. J. Biol. Chem. 2000, 275 (15), 10761–10766. https://doi.org/10.1074/jbc.275.15.10761. (362) Athauda, D.; Gulyani, S.; Karnati, H.; Li, Y.; Tweedie, D.; Mustapic, M.; Chawla, S.; Chowdhury, K.; Skene, S. S.; Greig, N. H.; et al. Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease. JAMA Neurol. 2019. https://doi.org/10.1001/jamaneurol.2018.4304. (363) Li, P.-C.; Liu, L.-F.; Jou, M.-J.; Wang, H.-K. The GLP-1 Receptor Agonists Exendin-4 and Liraglutide Alleviate Oxidative Stress and Cognitive and Micturition Deficits Induced by Middle Cerebral Artery Occlusion in Diabetic Mice. BMC Neurosci. 2016, 17 (1), 37. https://doi.org/10.1186/s12868-016-0272-9. (364) Tsaia, T. H.; Sun, C. K.; Su, C. H.; Sung, P. H.; Chua, S.; Zhen, Y. Y.; Leu, S.; Chang, H. W.; Yang, J. L.; Yip, H. K. Sitagliptin Attenuated Brain Damage and Cognitive Impairment in Mice with Chronic Cerebral Hypo-Perfusion through Suppressing Oxidative Stress and Inflammatory Reaction. J. Hypertens. 2015, 33 (5), 1001–1013. https://doi.org/10.1097/HJH.0000000000000529. (365) Kim, J. Y.; Lim, D. M.; Moon, C.; Jo, K. J.; Lee, S. K.; Baik, H. W.; Lee, K. H.; Lee, K. W.; Park, K. Y.; Kim, B. J. Exendin-4 Protects Oxidative Stress-Induced β-Cell Apoptosis through Reduced JNK and GSK3β Activity. J. Korean Med. Sci. 2010, 25 (11), 1626–1632. https://doi.org/10.3346/jkms.2010.25.11.1626. (366) Oeseburg, H.; De Boer, R. A.; Buikema, H.; Van Der Harst, P.; Van Gilst, W. H.; Silljé, H. H. W.



Glucagon-like Peptide 1 Prevents Reactive Oxygen Species-Induced Endothelial Cell Senescence through the Activation of Protein Kinase A. Arterioscler. Thromb. Vasc. Biol. 2010, 30 (7), 1407– 1414. https://doi.org/10.1161/ATVBAHA.110.206425. (367) Yang, J.-L.; Chen, W.-Y.; Chen, Y.-P.; Kuo, C.-Y.; Chen, S.-D. Activation of GLP-1 Receptor Enhances Neuronal Base Excision Repair via PI3K-AKT-Induced Expression of Apurinic/Apyrimidinic Endonuclease 1. Theranostics 2016, 6 (12), 2015–2027. https://doi.org/10.7150/thno.15993. (368) Yang, J. L.; Tadokoro, T.; Keijzers, G.; Mattson, M. P.; Bohr, V. A. Neurons Efficiently Repair Glutamate-Induced Oxidative DNA Damage by a Process Involving CREB-Mediated upRegulation of Apurinic Endonuclease 1. J. Biol. Chem. 2010, 285 (36), 28191–28199. https://doi.org/10.1074/jbc.M109.082883. (369) Yang, J. L.; Lin, Y. T.; Chuang, P. C.; Bohr, V. A.; Mattson, M. P. BDNF and Exercise Enhance Neuronal DNA Repair by Stimulating CREB-Mediated Production of Apurinic/Apyrimidinic Endonuclease 1. NeuroMolecular Med. 2014, 16 (1), 161–174. https://doi.org/10.1007/s12017013-8270-x. (370) Darsalia, V.; Mansouri, S.; Ortsäter, H.; Olverling, A.; Nozadze, N.; Kappe, C.; Iverfeldt, K.; Tracy, L. M.; Grankvist, N.; Sjöholm, Å.; et al. Glucagon-like Peptide-1 Receptor Activation Reduces Ischaemic Brain Damage Following Stroke in Type 2 Diabetic Rats. Clin. Sci. 2012, 122 (10), 473– 483. https://doi.org/10.1042/CS20110374. (371) Hyun Lee, C.; Yan, B.; Yoo, K. Y.; Choi, J. H.; Kwon, S. H.; Her, S.; Sohn, Y.; Hwang, I. K.; Cho, J. H.; Kim, Y. M.; et al. Ischemia-Induced Changes in Glucagon-like Peptide-1 Receptor and Neuroprotective Effect of Its Agonist, Exendin-4, in Experimental Transient Cerebral Ischemia. J.

Neurosci. Res. 2011, 89 (7), 1103–1113. https://doi.org/10.1002/jnr.22596. (372) Kim, S.; Moon, M.; Park, S. Exendin-4 Protects Dopaminergic Neurons by Inhibition of Microglial Activation and Matrix Metalloproteinase-3 Expression in an Animal Model of Parkinson’s Disease.

J. Endocrinol. 2009, 202 (3), 431–439. https://doi.org/10.1677/JOE-09-0132. (373) Gullo, F.; Ceriani, M.; D’Aloia, A.; Wanke, E.; Constanti, A.; Costa, B.; Lecchi, M. Plant Polyphenols and Exendin-4 Prevent Hyperactivity and TNF-α Release in LPS-Treated In Vitro Neuron/Astrocyte/Microglial Networks. Front. Neurosci. 2017, 11, 500. https://doi.org/10.3389/fnins.2017.00500. (374) Shiraishi, D.; Fujiwara, Y.; Komohara, Y.; Mizuta, H.; Takeya, M. Glucagon-like Peptide-1 (GLP-1) Induces M2 Polarization of Human Macrophages via STAT3 Activation. Biochem. Biophys. Res.

Commun. 2012, 425 (2), 304–308. https://doi.org/10.1016/j.bbrc.2012.07.086. (375) Wu, H.-Y.; Tang, X.-Q.; Liu, H.; Mao, X.-F.; Wang, Y.-X. Both Classic Gs-CAMP/PKA/CREB and Alternative Gs-CAMP/PKA/P38β/CREB Signal Pathways Mediate Exenatide-Stimulated Expression of M2 Microglial Markers. J. Neuroimmunol. 2018, 316, 17–22. https://doi.org/10.1016/j.jneuroim.2017.12.005.


Page 66 of 68

Page 67 of 68 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(376) Ghosh, A.; Roy, A.; Liu, X.; Kordower, J. H.; Mufson, E. J.; Hartley, D. M.; Ghosh, S.; Mosley, R. L.; Gendelman, H. E.; Pahan, K. Selective Inhibition of NF-KappaB Activation Prevents Dopaminergic Neuronal Loss in a Mouse Model of Parkinson’s Disease. Proc. Natl. Acad. Sci. 2007, 104 (47), 18754–18759. https://doi.org/0704908104 [pii]\n10.1073/pnas.0704908104. (377) Mattson, M. P.; Camandola, S. NF-ΚB in Neuronal Plasticity and Neurodegenerative Disorders.

Journal of Clinical Investigation. American Society for Clinical Investigation February 2001, pp 247–254. https://doi.org/10.1172/JCI11916. (378) Kenakin, T.; Christopoulos, A. Signalling Bias in New Drug Discovery: Detection, Quantification and Therapeutic Impact. Nature Reviews Drug Discovery. Nature Publishing Group February 15, 2013, pp 205–216. https://doi.org/10.1038/nrd3954. (379) Hager, M. V.; Clydesdale, L.; Gellman, S. H.; Sexton, P. M.; Wootten, D. Characterization of Signal Bias at the GLP-1 Receptor Induced by Backbone Modification of GLP-1. Biochem.

Pharmacol. 2017, 136, 99–108. https://doi.org/10.1016/j.bcp.2017.03.018. (380) Koole, C.; Savage, E. E.; Christopoulos, A.; Miller, L. J.; Sexton, P. M.; Wootten, D. Minireview: Signal Bias, Allosterism, and Polymorphic Variation at the GLP-1R: Implications for Drug Discovery. Mol. Endocrinol. 2013, 27 (8), 1234–1244. https://doi.org/10.1210/me.2013-1116. (381) Smith, J. S.; Rajagopal, S. The β-Arrestins: Multifunctional Regulators of G Protein-Coupled Receptors. J. Biol. Chem. 2016, 291 (17), 8969–8977. https://doi.org/10.1074/jbc.R115.713313. (382) Hager, M. V; Johnson, L. M.; Wootten, D.; Sexton, P. M.; Gellman, S. H. β-Arrestin-Biased Agonists of the GLP-1 Receptor from β-Amino Acid Residue Incorporation into GLP-1 Analogues.

J. Am. Chem. Soc. 2016, 138 (45), 14970–14979. https://doi.org/10.1021/jacs.6b08323. (383) Wootten, D.; Miller, L. J.; Koole, C.; Christopoulos, A.; Sexton, P. M. Allostery and Biased Agonism at Class b g Protein-Coupled Receptors. Chemical Reviews. 2017, pp 111–138. https://doi.org/10.1021/acs.chemrev.6b00049. (384) Quoyer, J.; Longuet, C.; Broca, C.; Linck, N.; Costes, S.; Varin, E.; Bockaert, J. L.; Bertrand, G.; Dalle, S. GLP-1 Mediates Antiapoptotic Effect by Phosphorylating Bad through a β-Arrestin 1Mediated ERK1/2 Activation in Pancreatic β-Cells. J. Biol. Chem. 2010, 285 (3), 1989–2002. https://doi.org/10.1074/jbc.M109.067207. (385) Freeman, J. L. R.; Dunn, I. M.; Valcarce, C. Beyond Topline Results for the Oral (NonPeptide)GLP-1R Agonist TTP273 in Type 2 Diabetes: How Much and When? Diabetol. Conf. 53rd

Annu. Meet. Eur. Assoc. study diabetes, EASD 2017. Port. 2017, 60 (1 Supplement 1), S51‐S52. https://doi.org/10.1007/s00125-017-4350-z. (386) Jorgensen, R.; Martini, L.; Schwartz, T. W.; Elling, C. E. Characterization of Glucagon-Like Peptide-1 Receptor β-Arrestin 2 Interaction: A High-Affinity Receptor Phenotype. Mol. Endocrinol. 2005, 19 (3), 812–823. https://doi.org/10.1210/me.2004-0312. (387) Bruno, B. J.; Miller, G. D.; Lim, C. S. Basics and Recent Advances in Peptide and Protein Drug Delivery. Therapeutic Delivery. NIH Public Access November 2013, pp 1443–1467.



https://doi.org/10.4155/tde.13.104. (388) Freeman, J. L.; Agolory, J.; Valcarce, C. Preclinical Findings with Oral GLP-1 Receptor Agonist TTP273 Reinforce Importance of Neuro-Enteroendocrine Signaling. In American Diabetes

Association 76th Annual Scientific Session; New Orleans, 2016.


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