Novel Targets for Parkinson's Disease: Addressing Different

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Review

Novel targets for Parkinson’s Disease: Addressing different therapeutic paradigms and conundrums Pallavi Rane, Deepaneeta Sarmah, Shashikala Bhute, Harpreet Kaur, Avirag Goswami, Kiran Kalia, Anupom Borah, Kunjan R. Dave, Nutan Sharma, and Pallab Bhattacharya ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00180 • Publication Date (Web): 29 Jun 2018 Downloaded from http://pubs.acs.org on June 30, 2018

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ACS Chemical Neuroscience

1

Novel targets for Parkinson’s Disease:

2

paradigms and conundrums

Addressing different therapeutic

3 4 5 6 7 8 9 10 11 12 13

Pallavi Rane1, Deepaneeta Sarmah1, Shashikala Bhute1, Harpreet Kaur1, Avirag Goswami2, Kiran Kalia1,Anupom Borah3,Kunjan R Dave2,Nutan Sharma4*,Pallab Bhattacharya1* 1

Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat-382355, India.2Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA. 3Department of Life Science and Bioinformatics, Assam University, Assam, India 4Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

14 15

*Corresponding author:

16 17

Pallab Bhattacharya, Ph. D

18

Assistant Professor and I/C Dean,

19

National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad

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Gandhinagar-382355, Gujarat, India.

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Email: [email protected]

22

[email protected]

23 24 25 26 27

* NS and PB have equal seniority in this study.

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ACS Paragon Plus 1 Environment

ACS Chemical Neuroscience 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

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Abstract

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Parkinson’s disease (PD) is a neurodegenerative disease that is pathologically

3

characterized by degeneration of dopamine neurons in the substantia nigra pars

4

compacta (SNpc).PD leads to clinical motor features that include rigidity, tremor and

5

bradykinesia. Despite multiple available therapies for PD, the clinical features continue

6

to progress, and patients suffer progressive disability. Many advances have been made

7

in PD therapy which directly target the cause of the disease rather than providing

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symptomatic relief. A neuroprotective or disease modifying strategy that can slow or

9

cease clinical progression and worsening disability remains as a major unmet medical

10

need for PD management. The present review discusses potential novel therapies for

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PD thatincludesrecent interventions in the form of immunomodulatory techniques and

12

stem cell therapy.Further, an introspective approach toidentify numerous other novel

13

targets that can alleviate PD pathogenesis and enable physicians to practice multi-

14

targeted therapy are discussed that may provide a ray of hope to PD patients in future.

15 16 17 18 19 20 21

Parkinson’s

disease,

22

Keywords:

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Neuroregeneration,Neuroprotection.

Neuroinflammation,Immunization,

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1

1.0 Introduction

2

Parkinson’s disease (PD) is the second most prevalent progressive neurodegenerative

3

disorder around the globe. PD is characterized by resting tremor, bradykinesia, muscle

4

rigidity, postural instability and akinesia along with depression, dementia, insomnia,

5

speech impairments and dysphagia in certain cases 1. Other associated problems are

6

improper functioning of the bladder and gastro intestinal tract (GIT), algesia, and visual

7

hallucinations. The neurodegeneration in PD not only affects the nigrostriatal

8

dopaminergic pathway but also result in changes in other neuronal pathways2. Etiology

9

may be associated with increasing age, gender, genetic background, environmental

10

exposure, nutritional deficiency and brain injury 3.

11

Epidemiological studies report that PD affects approximately 1% of the population

12

above the age of 55 years4. Currently, ten million people in the world are suffering from

13

this disease, and it is the 14th leading cause of death in the United States, spending

14

nearly $25 billion on PD treatment per year 5,6.

15

Several proteins and mechanisms have been identified in the pathogenesis of PD. The

16

aggregation and accumulation of misfolded or damaged proteins such as alpha

17

synuclein (αS) either plays a role in the loss of dopaminergic (DA) neurons or serves as

18

a marker of dying DA neurons. Mutations in genes including Leucine-rich repeat kinase

19

2 (LRRK2), glucocerebrosidase (GBA), PTEN-induced kinase 1 (PINK-1) andDaisuke-

20

Junko-1 (DJ-1) have been identified as the cause of some cases of PD7, 8.The present

21

review is focused on neuroprotection and neuroregeneration strategies for the treatment

22

of PD, as currently there are no marketed drugs that are effective in these areas.

23

Further, we discuss novel therapeutic targets along with their practical applications and

24

promising effects in combination with traditional methods to relieve the symptoms of PD.

25 26

2.0 Pathophysiology

27

2.1 Genetic basis



1

‘Parkinsonism’ is a broad term defined as the decrease in dopamine levels in the basal

2

ganglia due to the presence of lesions, particularly in the substantianigra9. There are

3

multiple mechanisms involved in the development of PD (Figure 1). The αS gene,

4

which is responsible for synaptic vesicle recycling, plays an essential role. Mutations in

5

the αS gene, A53T, A30P or E46K, lead to impairment of dopamine storage10-14. These

6

mutations eventually lead to the aggregation of abnormal fibrillar αS in Lewy bodies

7

(LBs). LBs either cause damage and death of substantia nigra pars compacta (SNpc)

8

DA neurons or serve as a marker of dying cells. Studies have reported that not only do

9

mutated forms of αS cause damage, but the expression of elevated levels of wild type

10

αS can also lead to degeneration of DA neurons15, 16.

11

Mutations of the GBA gene (L444P and N370S), which causes Gaucher’s disease, a

12

glycolipid storage disorder, has also been reported to induce the formation of Lewy

13

bodies in the brain

14

primarily affects mononuclear phagocytes, which become engorged with stored lipids. In

15

those who are heterozygous for a mutation in the GBA gene, there is an increased risk

16

of developing PD.It has been postulated that these genetic mutations lead to enhanced

17

protein aggregation or lysosmal dysfunction or a loss of function related to fluctuations

18

in levels of ceramide causing PD 17.

19

Mutations in another gene, LRRK2, are postulated to result in PD via a different

20

mechanism. The LRRK2 gene (also known as PARK8) codes for dardarin, a protein

21

with multiple functions including a leucine-rich region that likely is involved in protein-

22

protein interactions and two distinct enzymatic domains; phosphorylation by a kinase

23

domain and GTP-GDP hydrolysis by a ROC domain. LRKK2 is also involved in cellular

24

functions such as neurite outgrowth, cytoskeletal maintenance, vesicle trafficking,

25

autophagic protein degradation18. Missense mutations of LRKK2(R1441G, R1441C,

26

N1437H, Y1699C, G2019S andI2020T) lead to excitotoxicity due to increase in kinase

27

activity. Of all the known missense mutations, G2019S is the most common14.

28

2.2 Mitochondrial dysfunction and oxidative stress

17

. Gaucher’s disease is an autosomal recessive disorder that


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1

Oligomeric αS aggregation within the mitochondria induces its fragmentation. This

2

fragmentation

3

tetrahydropyridine), rotenone or oxidative stress. Fragmented mitochondria is a

4

hallmark of dysfunctional mitochondria. PINK1 and parkin, as studies have revealed,

5

may have a critical role in mitochondrial fragmentation and its elimination via mitophagy

6

(Figure2a)19-23.PINK1 is recruited and accumulated over the outer membrane of the

7

damaged mitochondria, which then recruits and activates protein parkin (E3 ubiquitin

8

ligase) which is involved in the ubiquitin proteasome system (UPS) degradation

9

pathway. Ubiquitination of the outer membrane bound mitofusin (Mfn-fusion prone

10

protein) in a parkin dependent manner leads to its degradation via the UPS, which

11

together with dynamin related protein1 (Drp1-regulates mitochondrial fission), initiates

12

the fragmentation of the damaged mitochondria

13

engulfed within autophagosomes and then delivered to lysosomes for mitophagy.

14

Another outer membrane protein miro, involved in the anterograde mitochondrial

15

transport along the axon, is also degraded by the above mentioned mechanisms 22, 25-28.

16

Miro degradation limits the transport of damaged mitochondria towards the terminus

17

and expels the fragmented mitochondria by mitophagy. Mutations within the PINK1 and

18

parkin genes may jeopardize the regulatory pathways and mitochondrial dynamics

19

leading to deregulated mitophagy and accumulation of damaged mitochondria

20

1 have also been found to be involved in mitochondrial dysfunction.DJ-1 gene codes for

21

cytosolic proteins. It acts as an antioxidant and protects neurons from oxidative damage

22

30

23

mutation in this gene leads to neurodegeneration 14.

24

2.3 Autophagy-lysosome system dysfunction

25

Autophagy and chaperone mediated autophagy (CMA) have an important role in the

26

pathogenesis of PD (Figure 2b)31. Autophagosomes are involved in the removal of

27

unwanted

28

autophagosomes engulf these materials prior to delivery to lysosomes containing a

29

milieu of hydrolytic enzyme for degradation. CMA is involved in the degradation of

30

specific soluble cytosolic proteins which contains motif recognized by the heat shock

31

cognate protein 70 (HSC70)

may

also

be

induced

by

MPTP

(1-methyl-4-phenyl-1,2,3,6-

24

. These damaged mitochondria are

28, 29

. DJ-

. It is prominently expressed in the cytoplasm, mitochondria, and nucleus, but a

or

damaged

cellular

components

or

32

organelles,

wherein

these

. Substrates for CMA include wild type αS, while the



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32-34

1

process is inhibited by modified αS

2

of the lysosome-associated membrane protein type 2A (LAMP 2A) receptor, a CMA

3

receptor. Substrate proteins specifically bind to lysosomal membranes through the

4

LAMP 2A receptor. The number of autophagosomes are increased in the DA neurons of

5

PD patients. Atg7 protein is the protein responsible for autophagosome formation and

6

deletion of the Atg7 gene in DA neurons delay its degeneration. Atg7 dysfunction

7

induces UPS for compensating the deficits of autophagy 35, 36. There is an accumulation

8

of LC3 (autophagosome inner membrane component), following loss of DJ-1

9

A53T mutation also induces neuronal death by promoting mitophagy38. The LRRK2

10

protein maintains the acidic environment within the lysosome and the autophagosome

11

numbers. Following treatment with (1-methyl-4-phenylpyridinium) MPP+ release of

12

lysosomal proteases are seen, which is inhibited by BCl2 associated X (BAX) and

13

reactive

14

endosomal/lysosomal proteins, GBA, vacuolar protein sorting-35 (VPS35) and type 5 P

15

type ATPase ATP13A2 lead to PD. αS accumulation is seen in DA neurons deficient in

16

VPS35, contained large endosome/lysosome and

17

endosome to golgi LAMP-2 A CMA receptor

18

impaired catabolism of lysosome and αS accumulation

19

degraded by lysosomes with the involvement of GBA and individuals carrying a single

20

mutant allele of GBA are at higher PD risk 42. Although, PD patients have reduced GBA,

21

irrespective of the patients harbouring the mutation 43.

22

3.0 Current available therapies

23

Levodopa is the first drug that was developed for PD and is used throughout the

24

world44. In the brain, levodopa crosses the blood-brain barrier (BBB) and is converted

25

into dopamine by the cells of the SNpc. The SNpc cells then release dopamine, acting

26

predominantly on striatal medium spiny neurons(Figure3). However, a relatively large

27

quantity of levodopa is required to be administered in oral form, as it is rapidly

28

metabolized in the periphery. To compensate, levodopa is administered along with

29

carbidopa. Carbidopa inhibits the metabolism of levodopa in the periphery, allowing a

30

greater proportion of levodopa to cross the blood brain barrier and exert its effects in the

31

central nervous system. Levodopa is most effective in reducing the motor symptoms

oxygen

species

(ROS)24.

. Mutations in LRRK2 and αS alter the function

Mutations

within

the

genes

37

for

. αS

the

exhibited impaired retrieval of

39, 40

. Functional ATP13A2 loss results in


41

. Glucosylceramide (GC) is

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1

associated with PD patients, however, as the disease progresses, levodopa becomes

2

effective for shorter and shorter periods. The reduction in levodopa efficacy isknown as

3

wearing off or the On-Off phenomenon, in which duration of the clinical benefit with

4

levodopa dose (On phase) becomes shorter. Other treatments, commonly used in

5

conjunction with carbidopa and levodopa, can be helpful in maximizing the period during

6

which rest tremor and rigidity are reduced.

7

Inhibitors of catechol-O-methyl transferase (COMT) (Entacapone, Tolcapone)and

8

inhibitors of monoamine oxidase B (MAO-B) (Selegiline, Rasagiline) serve to enhance

9

the effect of levodopa by reducing its metabolism45. However, as the disease

10

progresses, the effectiveness of levodopa is reduced.

11

In addition to delivering the precursor of dopamine to the brain, dopamine agonists are

12

used to bind to DA receptors and minimize the motor symptoms of PD. Four dopamine

13

agonists are used throughout the world; pergolide, bromocriptine, pramipexole and

14

ropinirole. Pergolide and bromocriptine were developed first and have broader receptor

15

activity than the newer agents. Pergolide is a D1 and D2 receptors agonist46while

16

bromocriptine is an agonist with somewhat greater affinity for D2 receptors.Further,

17

pergolide and bromocriptine both are ergot derived dopamine agonists reported to

18

cause valvular heart disease through their action on 5-HT2B receptors that are

19

expressed on heart valves

20

ropinirole, are more specific in their actions and limited evidence indicates that their use

21

may help to give patients a longer period of time before the wearing-off phenomenon

22

begins49, 50.Likewise, other dopamine agonists like rotigotine, lisuride and apomorphine

23

with longer half-lives are used to provide continuous dopaminergic stimulation by

24

altering the drug delivery system 51.

25

Amantadine is an N-methyl-D-aspartate (NMDA) receptor antagonist which also acts by

26

increasing dopamine release, having lesser side effects as compared to the above

27

therapies. Parkinson patients may also be treated with anticholinergics (atropine,

28

benztropine)for improved tremor control (Figure 3)10.

47, 48

.The newer dopamine agonists, pramipexole and



1

Deep brain stimulation (DBS), a surgical technique was developed for PD and was

2

approved as a therapy by the FDA in 2002 52, 53. This involves the insertion of electrodes

3

in either the subthalamic nucleus or the internal segment of the globus pallidus that

4

delivers electrical stimuli to modify or interrupt the pattern of neural signaling. It is

5

thought to act by inhibiting cells in the region surrounding the electrodes. However, the

6

precise mechanism by which DBS exerts its effect is unknown. DBS improves the

7

quality of life of PD patients by increasing the amount of time spent, each day, with

8

better motor performance. Risks associated with the surgery may be infection and

9

intracranial hemorrhage 53.

10

Electromagnetic therapy (EMT) is an alternative, safe and non-invasive approach for the

11

management of PD54. Transcranial magnetic stimulation (TMS), pulsed electromagnetic

12

therapy (PEMT), repetitive transcranial magnetic stimulation (RTMS) and high

13

frequency transcranial magnetic stimulation (HFTMS) are the different forms of EMT

14

which have been employed for use for management of PD54. These EMTs are said to

15

show their effects by inducing changes within the brain network and positively affect the

16

basal ganglia. Stimulation within the cortical region, mainly the prefrontal cortex and

17

primary motor cortex, indirectly modulate the release of DA from the striatal neurons

18

within the basal ganglia55. This release of DA in turn brings about improvement in the

19

motor symptoms of PD. EMT protocols can be molded as per the PD patient’s need.

20

Various parameters are to be taken into consideration before designing an EMT

21

protocol like the duration, frequency, stimulation intensity, pattern of stimulation, etc.

22

EMT approach can be used solo or can be combined with any of the conventional

23

treatment strategies to maintain the motor and non-motor PD symptoms54.

24

4.0 Novel therapeutic strategies to treat Parkinson’s disease

25

To gain deeper knowledge about the disease a number of experimental models have

26

been developed to genetically or chemically induce PD. Chemical agents, used to

27

recapitulate some of the features of PD in animals, includeMPTP, 6-hydroxydopamine

28

(6-OHDA), rotenone and paraquat 56. However, none of the available models are able to

29

replicate the full spectrum of physical symptoms and neuropathology found in


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1

humans57. Thus, animal models of PD are of limited utility in the development of novel

2

therapeutics.

3

The current treatments provide only symptomatic relief with numerous side effects.

4

There is no treatment available that halts or slows the progression of disease. Hence, it

5

is important to identify new targets with lesser side effects and the potential to slow

6

progression of PD. Potential novel therapies such asimmunization, stem cell

7

implantation and other new targets for oral medication including NADPH oxidase,

8

glutamate receptors and serotonergic receptors may be beneficial.

9

4.1 Promoting Neuroprotection

10

Ca2+plays an important role in thesurvival of neuronal cells. Dysregulation in Ca2+ levels

11

may lead to neurodegeneration. Reports suggests that an increase in brain Ca2+ levels

12

promotes aggregation of αS58. Hence, L-type calcium channel blockers such as

13

isradipine, which decrease brain Ca2+ levels may promote neuroprotection in PD. A

14

phase 3 study of the efficacy of isradipine in early PD is currently being conducted59.

15

Glucagon-like peptide 1 (GLP-1) may also be useful for PD patients. GLP-1suppresses

16

microglial activation and inflammation, enhancing mitochondrial biogenesis and

17

clearance of aggregated proteins

18

expression of insulin-degrading enzyme (IDE), a zinc-metalloendopeptidase that helps

19

in degrading insulin and other small peptides that forms β-pleated sheets. IDE is

20

activated by phosphoinositide 3-kinase (PI3K) and this inhibits αS fibril formation in vitro

21

by binding to αS oligomers, blocking them from forming fibrils60, 62.

22

Studies have shown that GLP-1 is secreted in the brain which acts on GLP-1 receptors.

23

GLP-1 agonist exendin-4 (exenatide) and its different synthetic analogs have been used

24

in PD as they are resistant to dipeptidyl peptidase IV (DPP-IV) action which is

25

responsible for metabolizing endogenous GLP-1

26

these drugs restored the levels of dopamine and improved motor function in vivo.

27

The potential neuroprotective effects of exendin-4, a GLP-1 agonist, havebeen

28

associated with modifications in intracellular calcium levels and anincreaseinMfn2.

60, 61

. Geniposide, a GLP-1 analogue increases the

61, 63

. Results have also shown that



Page 10 of 39

1

Mfn2enhancesendoplasmic reticulum–mitochondria coupling, as the accumulation of αS

2

causes mitochondrial fragmentation and/or damage by reducing this ER–mitochondrial

3

connectivity64. Exendin-4 prevents microglia activation, suppresses proinflammatory

4

cytokine production and also restores dopamine and tyrosine hydroxylase (TH) activity

5

in lipopolysaccharide (LPS) and MPTP-induced PD models65,

6

been approved for phase 3 clinical trials

7

κB, involved in PD pathogenesis is inhibited by Exendin-4, reducing neuroinflammation

8

and improving cell viability 69.

9

Recently, it has been proved that exendin-4 shows positive effects on PD patients in

66

. Exendin-4 and has

67, 68

. A transcription factor nuclear factor (NF)-

70

10

clinical trial but the underlying mechanism is still unknown

11

liraglutide and lixisenatide are the GLP-1 agonists with longer biological half-life were

12

tested in preclinical model of PD and both the drugs have shown neuroprotective effect

13

superior to the exendin-4 71.

14

Niacin, a precursor of nicotinamide adenine dinucleotide (NADH) and nicotinamide

15

adenine dinucleotide phosphate (NADPH) are required for dopamine synthesis72 which

16

are usually depleted in PD due to the administration of levodopa. GPR109A (niacin

17

receptor agonists), has demonstrated anti-inflammatory action via (NF)-κB, hence, may

18

protect DA neurons from damage and prevent disease progression72, 73.

19

It has been shown that activation of peroxisome proliferator-activated receptor-γ

20

(PPARγ), a member of the nuclear receptor superfamily, reduces inflammatory

21

responses in vitro and in vivo by protecting cells from death and toxicity74. It plays a role

22

in lipid homeostasis, glucose metabolism, inflammation, cellular differentiation and

23

proliferation.

24

neurodegenerative diseases like PD in C57BL/6 mice, alzheimer’s disease in APPV717I

25

mice

26

neurons from degeneration, inhibits microglial activation and monoamine oxidase

27

(MAO) enzyme activity in the striatum of rodent models of PD

28

neuronal glucose uptake and restores ATP levels in the brain78.

75

PPARγ

agonists

have

and ischemia in wistar rats

shown

. Similar to exendin-4,

neuroprotective

effects

in

many

76

. Pioglitazone, a PPARγ agonist, protects DA


74, 77

. It also increases

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1

PPARγ also has a role protecting mitochondrial function. It helps to maintain

2

mitochondrial membrane potential by providing mitochondria with alternative substrates

3

for coupled electron transport and oxidative phosphorylation79, 80.Pioglitazone stabilizes

4

MitoNEET, an iron-sulfur containing outer mitochondrial membrane protein which

5

regulates oxidative capacity

6

it failed in phase 2 clinical trials

7

outcome is that toxin animal models are not reflective of PD pathogenesis.

8

Another possibility is that pioglitazone failed to reach the target nigral neurons in a high

9

enough concentration82. Another PPARγ agonist, rosiglitazone, also shows similar

81

.Despite promising results in mouse and monkey models, 74, 82, 83

. A possible explanation for the negative

84

10

action, thus inhibiting neurodegeneration

. PPARγ Coativator-1α (PGC-1α) is

11

important in driving and coordinating mitochondrial biogenesis and respiration, oxidative

12

phosphorylation, gluconeogenesis, glucose transport, glycogenolysis, peroxisomal

13

remodeling, fatty acid oxidation, and muscle fiber-type switching85. In PD, it shows

14

neuroprotective activity by increasing the levels of ROS-detoxifying enzymes, such as

15

superoxide dismutase (SOD) 1 and 2, catalase and glutathione peroxidase and has also

16

been proved in vivo 80. During aging, it is observed that levels of PGC-1α are decreased

17

due to reduction in the levels of sirtuin186. Hence, experiments have been carried out by

18

overexpressing PGC-1α in vitro and it has shown to protect cells by increasing the

19

levels of antioxidants. In vivo, it protects DA neurons by inhibiting mitochondrial

20

dysfunction87, 88.

21

Nuclear receptor-related 1 (Nurr1), is a nuclear receptor involved in both the

22

biosynthesis of dopamine and the survival of DA neurons89. Nurr1 has been shown to

23

enhance in vitro and in vivo transcription of TH which is the rate-limiting enzyme of

24

dopamine biosynthesis, and of GTP cyclohydrolase I (GCH1), the first enzyme in the

25

biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for TH activity

26

Decreased Nurr1 levels have been strongly associated with PD and reduced DA neuron

27

survival92. Nurr1 binds to DNA as a monomer, homodimer, or heterodimer with retinoid

28

X receptor (RXR)α or RXRγ. Because Nurr1 heterodimerizes with RXRα in midbrain DA

29

neurons, Spathis et al.93 have designed Nurr1:RXRα-selective lead molecule which has

30

been proven to prevent DA neuronal loss and striatal DA denervation in vivo93.

31


90, 91

.


Page 12 of 39

1

4.2 Disease modification by targeting mutated genes

2

The microtubule system (MT) is involved in mitosis94. It has been reported that

3

microtubule dysfunction takes place due to environmental toxins and is responsible for

4

the formation of αS in animals95. Hence, microtubule stabilizing agents (Cevipabulin,

5

Cyclostreptin,

6

thetreatment of PD 96, 97.

7

As discussed, distinct genetic mutations have been identified in theαS gene at A53T,

8

A30P and E46K sites in rare cases of familialPD.Polyphenols are available in many

9

natural compounds and have shown positive effects in inhibiting αS and in

10

disaggregating its oligomers98. Polyphenols convert insoluble oligomers into a soluble

11

form, thereby decreasing neurotoxicity

12

myricetin, epigallocatechin gallate (EGCG), nordihydroguaiaretic acid (NDGA) and black

13

tea extract have shown promising results and may prove to be potential drug molecules

14

in the future to inhibit and disaggregate αS which can help to treat PD 7.

15

Another potential method of clearing the brain of αS aggregates is via the use of specific

16

antibodies. Single chain fragment variable antibodies (ScFvs) are new agents for

17

therapy of PD. These consist of minimal antigen binding site, the VH and VL variable

18

domains, linked by a flexible polypeptide linker and can be used against misfolded αS

19

proteins45, 100. These antibodies can be expressed using bacterial and mammalian gene

20

expression system, intracellularly as well as through therapeutic gene delivery101. The

21

best part about ScFvs is their specificity as they go and bind specifically only to DA-

22

modified proteins which are important in the case of PD as αS misfolding is directly

23

involved in dopamine synthesis 45.

24

A genetic mutation in LRRK2 gene leads to increase in kinase activity responsible for

25

PD102. Till date anendogenous ligand for LRRK2 kinase inhibitor is not known, but it

26

may be considered as a good target for neuroprotective therapy103. Henderson et al.104

27

and Daher et al.105 evaluated the effect of LRRK2 kinase inhibitor PF-06447475 in vivo

28

and they obtained promising results104. This molecule has been reported to block Αs

29

toxicity probably by modulating neuroinflammatory processes that are responsible to

Laulimalide,

Peloruside,

Taccalonolide)

are

potential

agents

in

99

. Polyphenols like baicalein, scutellarin,


Page 13 of 39 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


105

1

cause dopaminergic neuronal degeneration

. Hence, LRRK2 kinase is a good target

2

and need to be explored.

3

Mitochondrial Transcription Factor A (TFAM), a mitochondrial protein, plays a role in

4

mitochondrial DNA (mtDNA) transcription and mtDNA maintenance. Mutation in mtDNA

5

has been found to be involved in PD pathogenesis. Currently, limited supportive data is

6

available but it canprove to be a future potential target for PD87, 106.

7

4.3 Strategy for Neuronal Regeneration

8

Reports suggest that levels of brain-derived neurotrophic factor (BDNF), glial-derived

9

neurotrophic factor (GDNF), and nerve growth factor (NGF) are decreased in PD

107

.

10

These agents help in the growth of DA neurons and is neuroprotective in nature. GDNF

11

has been used to regenerate TH positive nigral neurons in vivo108. There was an

12

improvement in motor functions seen as a result of increased dopamine levels. But the

13

study failed to produce similar results in clinical trials109. Neurturin, a GDNF analogue

14

has proved to be effective in animal models and is currently in clinical trials103, 110.

15

In vitro and in vivo experiments have shown that erythropoietin (EPO) can act as an

16

antioxidant, promote maturation of DA neurons, increase the level of dopamine and

17

show anti-inflammatory activity111. So, EPO receptor agonist can prove beneficial for

18

PD. Eltrombopag has shown very good activity in both in vitro and in vivo96.

19

Clinical trials for antioxidants like Vitamin E and MAO-B inhibitors (selegiline),were

20

conducted but the results were not satisfactory112. Vitamin-E conferred limited

21

neuroprotection while selegiline exhibited neuroprotective action by a mechanism

22

different from that of MAO-B inhibition. It acts through stimulation of neurotrophic factor

23

synthesis and induction of superoxide dismutase113. Also, coenzyme Q10, a cofactor

24

involved in electron transport chain in mitochondria has shown a positive

25

neuroprotective effect in rodent modelsbut has failed to show clinical benefits103, 114.

26

4.4 Immunization

27

Immunization may be a successful therapy for preventing PD115.It has been shown that

28

mice with fewerT cells have greater neuronal loss116.Theoretically,one can say that self



Page 14 of 39

1

antigen-stimulated T lymphocytes enter the damaged nigrostriatal tissues and generate

2

both neurotrophins and neurotrophic factors117. To prove this, Benner et al.

3

vaccinated MPTP intoxicated mice with copolymer-1 (Cop-1; Copaxone, glatiramer

4

acetate), a random amino acid polymer that generates nonencephalitic T cells used to

5

treat relapsing-remitting multiple sclerosis118,

6

cells are transferred to damaged brain regions, where they decreased microglial

7

response and increased GDNF. Results have shown that there is also an increase in

8

SNpc TH neuronal bodies and striatal fibers. Also, it has shown to generate TH1, TH2 or

9

TH3 which suppresses innate immunity by decreasing the production of cytokines and

10

generates neurotrophic factor receptors, tropomyosin receptor kinase B (trkB), and

11

tropomyosin receptor kinase C (trkC). Thus, vaccination strategy could prove successful

12

in providing neuroprotection by protecting DA neurons in PD118.

13

Bacillus Calmette-Guerin (BCG) vaccine (containing live attenuated Mycobacterium

14

bovis) can also be used for the treatment of PD. Experiments have shown that complete

15

Freund’s adjuvant (CFA) (containing inactivated Mycobacterium tuberculosis in mineral

16

oil) showed more immune stimulation rather than TH and Copaxone in CFA. But CFA is

17

unsuitable for human use. Hence, experiments were carried out to check whether BCG

18

can be used as a neuroprotective vaccine to prevent neurodegeneration120. Results

19

have shown that there is an increase in dopamine transporters and dopamine levels in

20

MPTP mouse model along with activation of Th1-type CD4+ T cells which is known to

21

antagonize the development of Th17 cells and induces apoptosis of self-reactive T cells,

22

thus providing neuroprotection. BCG also activates antigen presenting cells (APCs) and

23

induces the production of Regulatory T cells (Tregs) which cause a decrease in

24

inflammatory response. Another mechanism for neuroprotection is believed to be the

25

diversion of the T effectors and macrophages to the periphery and avoiding their

26

entrance to CNS. From the entire study authors concluded that BCG vaccination is a

27

safe treatment for preventing DA neuronal loss and providing neuroprotective effect121.

28

4.5 Stem Cell Therapy

29

Stem cells can differentiate into neurons, astrocytes and oligodendrocytes and after

30

transplantation they can move to and generate neurons at the site of injury. Apart from

118

119

. They showed that Cop-1 immunized


Page 15 of 39 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


1

regeneration of neurons, other mechanisms of protection by stem cells include

2

neuromodulatory and neuroprotective effects that are exhibited by the cells themselves

3

or by their secretions122. Induced pluripotent stem cells (iPSCs) are converted into

4

neural precursor cells which are further differentiated into neurons and glial cells, thus

5

improving behavior and motor function in vivo123. These cells can alsobe differentiated

6

into DA neurons in vitro.Along with these iPSCs, mesenchymal stem cells (MSCs), also

7

called as ‘marrow stromal cells,’ stimulate regeneration by promoting endogenous

8

neurogenesis and protects DA neurons by secretion of cytokines and nerve growth

9

factors from cells that create an environment favorable for neuroregeneration when

10

supplied with growth factors like BDNF, fibroblast growth factor 2 (FGF-2), epidermal

11

growth factor (EGF), NGF, insulin-like growth factor 1 (IGF-1), transforming growth

12

factor alpha (TGF-α), platelet-derived growth factor (PDGF), and vascular endothelial

13

growth factor (VEGF)

14

expression and dopamine content both in vitro and in vivo126. An important advantage

15

with MSCs are that they are immunoprivileged and have no ethical concerns for its

16

use127. Also, MSCs in the subventricular zone (SVZ) leads to a proliferation of

17

endogeneousprogenitors, and they also have anti-inflammatory and immunomodulatory

18

activities. Another mechanism for protection of DA neurons is the recovery of BBB,

19

which is compromised in PD

20

MSCs, can differentiate into neuronal cells and increase dopamine levels along with the

21

recovery of DA neurons due to improvement in mitochondrial function in vivo125.

22

Neural stem cells (NSC) and progenitor cells present in the SVZ is responsible for

23

constitutive neurogenesis. Dopamine levels are brought to normal by stimulating NSC

24

which can travel to the striatum and gets differentiated into DA neurons and can

25

decrease the motor symptoms of PD128. Results have shown that progenitor cells can

26

produce new neurons in vitro but not in vivo. There is an increase in DA neurons in

27

rodents, in primates and also in PD patients whohavebeen tested by measuring the

28

presence of TH-positive cells. TGF-αand exendin-4 have shown promising effects

29

onproliferation of progenitor cells in vitro. There has been an increase seen in a number

30

of neuroblasts in SVZ and striatum using a combination of EGF and FGF-2 treatment in

31

6-OHDA treated rats

124, 125

. These growth factors lead to increase in TH gene

124

.Human adipose-derived stem cells (hASCs), a type of

125

.Zuo et al.129, carried out studies to test the therapeutic efficacy



129

1

of NSCs in 6-OHDA model of PD

. NSCs showed improvement in motor and

2

cognitive activities as compared to lesion control animals. This behavioral improvement

3

was seen due to alterations in the proteome profile, neurotrophic factor secretion and

4

cytokine levels in the SVZ and functional improvements was due to stimulation of

5

neurogenesis in SVZ through the resident stem cells within this niche that initiated a

6

multi‐faceted brain regenerative machinery 129, 130.

7

Altarche-Xifro et al.131, carried out experiments to show that hematopoietic stem and

8

progenitor cells (HSPCs) can fuse with neurons and glial cells in vivo, get converted to

9

mature astroglia releasing neurotrophic factors and wnt1 which prevents the secretion

10

of proinflammatory cytokines131. These factors decrease DA neuronal degeneration but

11

do not help in regenerating new DA neurons. The major disadvantage of HSPCs is that

12

following one week of transplantation there is immune rejection, leading to a decrease

13

in the number of cells131. There are challenges with the use of stem cells that vary from

14

the choice of cells to the number of cells used for transplantation and timing of delivery.

15

Other challenges include dissecting the mechanisms by which these cells work, their

16

possible side effects and their immune rejection in the host body 122.

17

As per reports available on clinicaltrials.gov,20 trials have been reported wherein stem

18

cells have been transplanted in PD patients, of which 14 are active, status of 2 are

19

unknown and 2 have been either terminated or suspended. Only 1 of the listed trials has

20

been completed, however, the results are yet to be published. The first clinical trials with

21

stem cells in PD patients was reported in 1987, where human fetal mesencephalic

22

tissue rich in dopaminergic neuroblasts was transplanted intrastriatally to see whether

23

the transplanted cells could survive and re-establish functional connections in the

24

diseased area. Beneficial results were obtained as compared to the sham controls

25

however, uncontrollable dyskinesias were reported in few patients132. A controlled,

26

double blind trial with bilateral fetal nigral transplantation was carried out by Olanow et

27

al. No overall beneficial effect was seen and over fifty six percent of the patients

28

developed dyskinesia

29

Venkataramana et al. autologous bone marrow derived MSCs were transplanted.

30

Subjective improvement in symptoms were reported and no serious adverse effects

133

. In a prospective, uncontrolled trial carried out by


Page 16 of 39

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1

were observed following stem cell transplantation. Although, the effectiveness of the

2

treatment could not be assessed due to the uncontrolled nature of the trial. However,

3

results from this trial support and encourage future trials with larger patient number to

4

establish efficacy

5

cells for PD.

6

4.6 Targeting Neuroinflammation

7

As mentioned earlier, oxidative stress plays an important role in the pathogenesis of PD

8

leading to loss of DA neurons

9

producingenzyme complex in phagocytes playing an important role as a defense

10

mechanism136. As a result of ROS production, NADPH oxidase is activated and it takes

11

part in host defense, cellular signaling, stress response, and tissue homeostasis. The

12

overactivity of NOX2 (a subunit of NADPH which is present in phagocyte) increases

13

ROS production from activated microglia leading to oxidative stress due to

14

neuroinflammation and chronic neurodegeneration. Microglial activation releases

15

cytokines, chemokines, eicosanoids, ROS; of which NOX2 derived ROS, which is

16

increased due to aggregation of αS,plays a role inDA neurodegeneration137. Hydrogen

17

peroxide and peroxy nitrite from activated microglial NOX2 enters neurons, disrupts

18

mitochondrial function by decreasing ATP production and increasing ROS. Hence, there

19

is a need to inhibit NOX2 to protect DA neurons from degeneration. Drugs like

20

sinomenine, squamosamide derivative FLZ, pituitary adenylate cyclase-activating

21

polypeptides, transforming growth factor-b1 (TGF-b1), verapamil, andresveratrol. All

22

these drugs inhibited superoxide release from microglia in vitro138.

23

Neuroinflammation

24

phospholipaseA2 (PLA2) activity, due to increase in fatty acids and lysophospholipid

25

contents, which eventually develop into secondary messengers after a series of

26

metabolic steps. Many PLA2 inhibitors have been studied in rat models of PD and have

27

shown very potent activity against PD96, 139.

28

Non-steroidal anti-inflammatory drugs (NSAIDS) reduces the activity of cyclooxygenase

29

(COX) thus decreasing prostaglandin and inhibiting ROS and RNS generation140. It also

30

activates PPARγ which, as mentioned above, have anti-inflammatory properties. There

134

. Table 2 lists all major clinical trials investigating different stem

and

neural

135

. NADPH oxidase (PHOX) is a superoxide-

damage

may

also


result

from

increased


1

are many evidences which point out the neuroprotective effects of NSAIDS and can

2

protect DA neurons from degeneration

3

usedagainst neuroinflammation as their receptors are present on microglia which

4

activate (NF)-κB, responsible for inflammation142.

5

4.7 Other targets

6

A few novel targets have also been identified for therapy of PD (Table 1). One such

7

target is the angiotensin-2 peptide that activates angiotensin-1 receptor, increasing the

8

formation of NADPH and superoxide leading to microglial activation. Thus, angiotensin

9

is found to be involved in dopamine neuronal degeneration in substantia nigra, caudate

10

nucleus. Hence, Angiotensin-converting enzymes (ACE) inhibitors like Perindopril has

11

proved to be beneficial to treat PD

12

cyclic adenosine monophosphate (cAMP) in PD, whose levels are decreased in such

13

patients. Hence, inhibitors of phosphodiesterase 7 which is expressed in brain can

14

prove effective by increasing the cAMP levels due to the reduction of hydrolysis96, 144.

15

Serotonergic receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C) play an important role in

16

PD as they are involved in levodopa induced dyskinesia (LID). It has been proven in

17

clinical trials that 5HT1A receptor agonist sarizotan HC1 can help in treating LID145.

18

Caffeine, an adenosine receptor (A2a) antagonist, has shown good results in PD

19

patients146. A2a receptor heterodimerizes with the D2 receptor present in the brain which

20

inhibits signaling of dopamine. Hence, Adenosine receptor antagonist can be targeted

21

for PD

22

glycolytic enzyme whichplays a role in initiating apoptosis. Propargylamine TCH346 and

23

CEP-1347, GAPDH inhibitors has shown good results in vivofor PD but have failed in

24

clinical trials 103, 110.

25

Glutamate, which binds to NMDA receptors on DA neurons, plays a role in excitotoxicity

26

in PD. Activation of NMDA receptors causes an influx and increase in intracellular

27

calcium levels which, when uncontrolled, leads to cell death148. Hence, NMDA receptor

28

antagonists are potential therapeutic agents103, 110, 149, 150. α-amino-3-hydroxy-5-methyl-

29

4-isoxazolepropionic acid (AMPA) receptors also increase glutaminergic transmission.

30

So likewise, the use of AMPA receptor antagonists like 2,3-dihydroxy-6-nitro-7-

141

. Apart from these, glucocorticoids are also

96, 143

.Experiments have found the involvement of

103, 147

. Also, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a


Page 18 of 39

Page 19 of 39 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


1

sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) and GYKI 52466 can also inhibit

2

excitotoxicity, however, they failed to inhibit motor symptoms.Talampanel has

3

successfully passed phase 2 clinical trials151. More molecules are needed to be

4

developed for this potential target152.

5

5.0 Conclusion

6

Current therapies for PD focus more on providing symptomatic relief, rather than

7

providing a means by which it can target the main pathology of the disease. Many

8

advances have been made in PD therapy as discussed. Of the newer approaches,

9

therapy based on stem cells may be promising. Majority of the questions that arise at

10

clinics may not be solely answered by preclinical studies, hence, further well designed

11

clinical studies are warranted to validate their efficacy and safety. Researchers should

12

also explore utilising combination therapies rather than focusing on single therapy to

13

treat PD patients for a better outcome.

14

Acknowledgement:

15

This work is supported by the Department of Pharmaceuticals, Ministry of Chemical and

16

Fertilizers, Govt. of India and National Institute of Pharmaceutical Education and

17

Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, India. Authors also want to

18

express their thanks to the Director, NIPER Ahmedabad for providing necessary

19

facilities and infrastructure.

20

Conflict of Interest:

21

The authors have no conflict of interest to declare.

22

Author Contributions

23

PR, DS, SB, AG, AB, NS, KD and PB conceived and designed the study. PR, DS, NS

24

and PB outlined the performed rigorous literature search. NS, AB KK and PB conceived

25

and designed the figures and images. PR, DS, AG,KD,NS and PB wrote the

26

manuscript. PR, DS, HK and PB worked on the rebuttal and addition of new sections.

27



Page 20 of 39

1

Figure legends:

2

Figure 1. Various pathways involved in the pathogenesis of PD. Mutation in αS and

3

GBA genes cause protein misfolding leading to lewy body formation. Along with it

4

LRRK-2 gene mutation causes excitotoxicity. Mutation in Parkin, PINK-1, and DJ-1

5

genes results in mitochondrial dysfunction and dopamine metabolism, both eventually

6

leading to an increase in oxidative stress due to free radical generation. As a result,

7

there is dopaminergic neuronal death in PD. GBA- Glucocerebrosidase, LRRK–2 -

8

Leucine-rich repeat kinase 2, PINK–1 - PTEN-induced kinase 1, DJ–1 - Daisuke-Junko-

9

1, ROS - Reactive oxygen species7, 8, 19.

10

Figure 2 (a)Mitochondrial dysfunction in Parkinson’s disease: In the presence of MPTP

11

,rotenone or α-synuclein aggregates, mitochondrial fragmentation takes place. PINK1

12

and parkin are said have a role to play in this process. Mitophagy eliminates the

13

damaged mitochondria. Ubiqitination of the outer membrane of the mitochondria leads

14

to its degradation via the ubiquitin proteasome system (UPS). PINK1: PTEN-induced

15

putative kinase 1; drp-1: Dynamin-1-like protein; miro: Mitochondrial Rho GTPase 1;

16

Mitofusin 1; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; DJ-1: Parkinson

17

disease protein 7; ROS: Reactive oxygen species; LC3: microtubule-associated protein

18

1 light chain 3; UPS: ubiquitin proteasome system; LRRK2: Leucine-rich repeat kinase

19

2; Atg7: Autophagy-related protein 714, 19-30.(b) Autophagy-lysosome system dysfunction

20

in Parkinson’s disease. Autophagosomes remove damaged cellular components and

21

deliver them to lysosomes having hydrolytic enzymes for degradation. Chaperone

22

mediated autophagy degrade specific cytosolic proteins. α-SYN:α-synuclein; HSC70:

23

heat shock cognate protein 70; LRRK2: Leucine-rich repeat kinase 2; LAMP-2A:

24

Lysosome-associated

25

glucosylceramide; ROS: Reactive oxygen species; BAX: Bcl-2-associated X protein;

26

VPS35: Vacuolar protein sorting-associated protein 35; ATP13A2: Probable cation-

27

transporting ATPase 13A2; MPP+: 1-Methyl-4-phenylpyridine31-43.

28

Figure 3.Currently available treatment for PD. Levodopa is commonly used in PD.

29

Along with it COMT, MAO-B, and DDC inhibitors are given in combination. Other drugs

30

like dopamine agonist and anticholinergics are also administered. COMT - catechol-O-

membrane

protein

2;

GBA:


Glucocerebrosidase;

GC:

Page 21 of 39 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


1

methyl transferase, MAO-B - Monoamine oxidase B, DDC - Dopa Decarboxylase, LAT-

2

L-amino acid transporter44-51.

3


ACS Chemical Neuroscience 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

Page 22 of 39

1

Table 1.Various approaches involved in the management of PD.(GLP-1-Glucagon-like peptide-2, PPAR-Peroxisome

2

proliferator-activated receptor, PGC-1α-Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, EGCG-

3

Epigallocatechin gallate, NDGA-Nordihydroguaiaretic acid, ScFvs-Single-chain variable fragment, LRRK2-Leucine-rich

4

repeat kinase 2, BDNF-Brain-derived neurotrophic factor, GDNF-Glial cell-derived neurotrophic factor, NGF-Nerve growth

5

factor, CoQ10-Coenzyme Q10, Cop-1- Copaxone, glatiramer acetate, HSPCs- Hematopoietic stem and progenitor cells,

6

PLA2- Phospholipase A2, TGF-β1-Transforming growth factor beta 1, 5HT1A-Serotonin 1A receptor, A2a- Adenosine

7

receptor

8

isoxazolepropionic acid, DBS-Deep brain stimulation, EMT- Electromagnetic therapy).

2

a,

GAPDH-Glyceraldehyde

Sl. No.

3-phosphate

dehydrogenase,

Approach

AMPA-α-amino-3-hydroxy-5-methyl-4-

Reference

Neuroprotection 1.

L-type Calcium channel blockers (isradipine)

58, 59

2.

GLP-1 analogue (Geniposide)

60, 62

3.

GLP-1 agonists (exenatide, liraglutide, lixisenatide)

4.

Niacin receptor agonists (GPR109A)

5.

PPARγ agonists (Pioglitazone, rosiglitazone)

6.

PGC-1α activators

85

7.

Nurr1:RXRα agonist

93

61, 63, 71 72, 73 74, 77, 78, 84

Targeting mutated genes 1.

Microtubule stabilizing agents (Cevipabulin, Cyclostreptin,


96, 97

Page 23 of 39 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


Laulimalide, Peloruside, Taccalonolide) 2.

Polyphenols (baicalein, scutellarin, myricetin, EGCG, NDGA and black tea extract)

3.

Specific antibodies (ScFvs)

4.

LRRK2 kinase inhibitor (PF-06447475)

7, 98

45 104, 105

Neuronal Regeneration 107

1.

Tropic factors (BDNF, GDNF, NGF)

2.

GDNF analogue (Neurturin)

3.

Erythropoietin analogue (Eltrombopag)

4.

Antioxidants (Vit E, CoQ10)

103, 110 96 112, 114

Immunization 1.

Cop-1 immunized cells

118

2.

BCG vaccine

121

Stem cells 1.

iPSCs

123

2.

MSCs

124, 126

3.

hASCs

125

4.

NSCs

125, 129



Page 24 of 39

5.

NPCs

128

6.

HSPCs

131

Targeting Neuroinflammation 1.

PLA2 inhibitors

139

2.

Superoxide release inhibitors (sinomenine, squamosamide derivative, sinomenine, squamosamide derivative, TGF-b1, verapamil, and resveratrol)

138

3.

NSAIDS (COX inhibitors)

4.

Glucocorticoids

140, 141 142

Others 1.

5HT1A receptor agonist (Sarizotan HC1)

145

2.

A2a antagonist (Caffeine)

146

3.

GAPDH inhibitors (Propargylamine, TCH346 and CEP-1347)

101, 108

4.

NMDA receptor antagonists

108, 150

5.

AMPA receptor antagonists (NBQX, GYKI 52466 and Talampanel)

151, 152

6.

DBS

53

7.

EMT

54

1


Page 25 of 39 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


1

Table 2. Clinical trials investigating different types of stem cell as a potential therapy for PD. (SCs-stem cells,

2

MSCs-mesenchymal stem cells, NSCs-neural stem cells, BM-bone marrow, AD adipose derived,

3

pluripotent stem cells, SVF-stromal vascular fraction, ESC-embryonic stem cells, NPC-neural progeneitor cells).

iPSCs-induced

Sl. No.

Trial ID

Country

Intervention

Status

Outcome Measures

1.

NCT00976430

India

BM-MSCs

Suspended

Safety and efficacy

2.

NCT03128450

China

NSCs

Enrolling

Safety and efficacy

3.

NCT03550183

China

MSCs

Recruiting

Safety and efficacy

4.

NCT01446614

China

BM-MSCs

Unknown

Safety and efficacy

5.

NCT02780895

Mexico

SCs

Active

N/A

6.

NCT02611167

United States

Allogeneic BM-MSCs

Recruiting

Safety, feasibility, and efficacy

7.

NCT01329926

Unites States

NSCs

Enrolling

N/A

8.

NCT03309514

N/A

N/A

Not yet recruiting

Safety and efficacy

9.

NCT02538315

Canada

N/A

Recruiting

N/A

10.

NCT01453803

United States

AD-SVF

Withdrawn

Safety and efficacy

11.

NCT02452723

Australia

NSCs

Recruiting

Safety

12.

NCT03119636

China

ESC-NPCs

Recruiting

Safety and efficacy

13.

NCT02184546

United States

AD-SCs

Active

N/A

14.

NCT00927108

Thailand

NSCs

Unknown

N/A

15.

NCT02511015

United States

N/A

Completed

N/A

16.

NCT02795052

United States

BM-MSCs

Recruiting

Efficacy



Page 26 of 39

and United Arab Emrates 17.

NCT03297177

United States

SCs

Recruiting

Safety and efficacy

18.

NCT00874783

Israel

iPSCs

Recruiting

N/A

19.

NCT01953523

United States

AD-SVF

Unknown

Safety and clinical outcomes

1 2


Page 27 of 39 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

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


Reference 1.

2. 3. 4.

5. 6. 7.

8.

9. 10. 11.

12.

13.

14. 15.

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1

For Table of Contents Use Only

2

Novel targets for Parkinson’s Disease:

3

paradigms and conundrums

4 5 6 7 8 9 10 11 12 13

Addressing different therapeutic

Pallavi Rane1, Deepaneeta Sarmah1, Shashikala Bhute1, Harpreet Kaur1, Avirag Goswami2,Kiran Kalia1,Anupom Borah3, Kunjan R Dave2, Nutan Sharma4*,Pallab Bhattacharya1* 1

Department of Pharmacology and Toxicology,National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat-382355, India.2Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USA. 3Department of Life Science and Bioinformatics, Assam University, Assam, India 4Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

14


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LRRK-2 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

Parkin, PINK-1, DJ-1 Alpha synuclein &GBA Genetic mutation

Protein misfolding

Figure-1

Lewy body formation ACS Paragon Plus Environment

Mitochondrial dysfunction

Dopamine

ROS

Figure 2a 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


Figure 2b

ACS Paragon Plus Environment

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Periphery

1 3-O-Methyldopa 2 3 4 Entacapone COMT 5 6 Levodopa 7 8 DDC 9 Carbidopa 10 11 Dopamine 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Figure-3 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41

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LAT


Brain

Deep brain stimulation

3-O-Methyldopa COMT

Entacapone

Cholinergic receptors

Anticholinergics

Levodopa Bromocriptine Dopamine Amantadine D1 and D2 receptors

Dopamine MAO-B

Selegiline

DOPAC

LIVER COMT 3-O-Methyldopa

DDC Levodopa

Entcapone

ACS Paragon Plus Environment

Dopamine

Carbidopa

Antipsychotics

Novel Targets for Parkinson's Disease: Addressing Different

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