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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
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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
20
Gandhinagar-382355, Gujarat, India.
21
Email:
[email protected] 22
[email protected] 23 24 25 26 27
* NS and PB have equal seniority in this study.
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Abstract
2
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
8
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
11
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:
23
Neuroregeneration,Neuroprotection.
Neuroinflammation,Immunization,
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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
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‘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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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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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
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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.
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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
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. Glucosylceramide (GC) is
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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
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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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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.
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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
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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
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74, 77
. It also increases
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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
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.
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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,
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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
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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
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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
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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
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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
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from
increased
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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
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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
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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:
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GC:
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1
methyl transferase, MAO-B - Monoamine oxidase B, DDC - Dopa Decarboxylase, LAT-
2
L-amino acid transporter44-51.
3
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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,
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ACS Chemical Neuroscience
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
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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
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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
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NCT02795052
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For Table of Contents Use Only
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Novel targets for Parkinson’s Disease:
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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.
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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
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Figure 2b
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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
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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
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Dopamine
Carbidopa
Antipsychotics