Incretin Mimetics as Rational Candidates for the Treatment of

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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.

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


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