Novel Targets for Parkinson's Disease: Addressing Different

Review Cite This: ACS Chem. Neurosci. 2019, 10, 44−57

pubs.acs.org/chemneuro

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. 2019.10:44-57. Downloaded from pubs.acs.org by OPEN UNIV OF HONG KONG on 01/28/19. For personal use only.

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Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat-382355, India ‡ Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States § Department of Life Science and Bioinformatics, Assam University, Silchar, Assam 788011, India ∥ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States ABSTRACT: Parkinson’s disease (PD) is a neurodegenerative disease that is pathologically characterized by degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc). PD leads to clinical motor features that include rigidity, tremor, and bradykinesia. Despite multiple available therapies for PD, the clinical features continue to progress, and patients suffer progressive disability. Many advances have been made in PD therapy which directly target the cause of the disease rather than providing symptomatic relief. A neuroprotective or disease modifying strategy that can slow or cease clinical progression and worsening disability remains as a major unmet medical need for PD management. The present review discusses potential novel therapies for PD that include recent interventions in the form of immunomodulatory techniques and stem cell therapy. Further, an introspective approach to identify numerous other novel targets that can alleviate PD pathogenesis and enable physicians to practice multitargeted therapy and that may provide a ray of hope to PD patients in the future are discussed. KEYWORDS: Parkinson’s disease, neuroinflammation, immunization, neuroregeneration, neuroprotection

1. INTRODUCTION Parkinson’s disease (PD) is the second most prevalent progressive neurodegenerative disorder around the globe. PD is characterized by resting tremor, bradykinesia, muscle rigidity, postural instability, and akinesia along with depression, dementia, insomnia, speech impairments, and dysphagia in certain cases.1 Other associated problems are improper functioning of the bladder and gastrointestinal tract (GIT), algesia, and visual hallucinations. The neurodegeneration in PD not only affects the nigrostriatal dopaminergic pathway but also result in changes in other neuronal pathways.2 Etiology may be associated with increasing age, gender, genetic background, environmental exposure, nutritional deficiency, and brain injury.3 Epidemiological studies report that PD affects approximately 1% of the population above the age of 55 years.4 Currently, 10 million people in the world are suffering from this disease, and it is the 14th leading cause of death in the United States, with spending being nearly $25 billion on PD treatment per year.5,6 Several proteins and mechanisms have been identified in the pathogenesis of PD. The aggregation and accumulation of misfolded or damaged proteins such as alpha synuclein (αS) either plays a role in the loss of dopaminergic (DA) neurons or serves as a marker of dying DA neurons. Mutations in genes including leucine-rich repeat kinase 2 (LRRK2), glucocere© 2018 American Chemical Society

brosidase (GBA), PTEN-induced kinase 1 (PINK-1), and Daisuke-Junko-1 (DJ-1) have been identified as the cause of some cases of PD.7,8The present review is focused on neuroprotection and neuroregeneration strategies for the treatment of PD, as currently there are no marketed drugs that are effective in these areas. Further, we discuss novel therapeutic targets along with their practical applications and promising effects in combination with traditional methods to relieve the symptoms of PD.

2. PATHOPHYSIOLOGY 2.1. Genetic Basis. “Parkinsonism” is a broad term defined as the decrease in dopamine levels in the basal ganglia due to the presence of lesions, particularly in the substantia nigra.9 There are multiple mechanisms involved in the development of PD (Figure 1). The αS gene, which is responsible for synaptic vesicle recycling, plays an essential role. Mutations in the αS gene, A53T, A30P, or E46K lead to impairment of dopamine storage. 10−14 These mutations eventually lead to the aggregation of abnormal fibrillar αS in Lewy bodies (LBs). LBs either cause damage and death of substantia nigra pars Received: April 16, 2018 Accepted: June 29, 2018 Published: June 29, 2018 44

DOI: 10.1021/acschemneuro.8b00180 ACS Chem. Neurosci. 2019, 10, 44−57

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ACS Chemical Neuroscience

Figure 1. Various pathways involved in the pathogenesis of PD. Mutation in αS and GBA genes cause protein misfolding leading to lewy body formation. Along with it LRRK-2 gene mutation causes excitotoxicity. Mutation in Parkin, PINK-1, and DJ-1 genes results in mitochondrial dysfunction and dopamine metabolism, both eventually leading to an increase in oxidative stress due to free radical generation. As a result, there is dopaminergic neuronal death in PD. GBA, glucocerebrosidase; LRRK-2, leucine-rich repeat kinase 2; PINK-1, PTEN-induced kinase 1; DJ-1, Daisuke-Junko-1; ROS, reactive oxygen species.7,8,19

hallmark of dysfunctional mitochondria. PINK1 and parkin, as studies have revealed, may have a critical role in mitochondrial fragmentation and its elimination via mitophagy (Figure2a).19−23PINK1 is recruited and accumulated over the outer membrane of the damaged mitochondria, which then recruits and activates protein parkin (E3 ubiquitin ligase) which is involved in the ubiquitin proteasome system (UPS) degradation pathway. Ubiquitination of the outer membrane bound mitofusin (Mfn-fusion prone protein) in a parkin dependent manner leads to its degradation via the UPS, which together with dynamin related protein1 (Drp1-regulates mitochondrial fission), initiates the fragmentation of the damaged mitochondria.24 These damaged mitochondria are engulfed within autophagosomes and then delivered to lysosomes for mitophagy. Another outer membrane protein miro, involved in the anterograde mitochondrial transport along the axon, is also degraded by the above-mentioned mechanisms.22,25−28 Miro degradation limits the transport of damaged mitochondria toward the terminus and expels the fragmented mitochondria by mitophagy. Mutations within the PINK1 and parkin genes may jeopardize the regulatory pathways and mitochondrial dynamics leading to deregulated mitophagy and accumulation of damaged mitochondria.28,29 DJ-1 have also been found to be involved in mitochondrial dysfunction.DJ-1 gene codes for cytosolic proteins. It acts as an antioxidant and protects neurons from oxidative damage.30 It is prominently expressed in the cytoplasm, mitochondria, and nucleus, but a mutation in this gene leads to neurodegeneration.14 2.3. Autophagy-Lysosome System Dysfunction. Autophagy and chaperone mediated autophagy (CMA) have an important role in the pathogenesis of PD (Figure 2b).31 Autophagosomes are involved in the removal of unwanted or

compacta (SNpc) DA neurons or serve as a marker of dying cells. Studies have reported that not only do mutated forms of αS cause damage, but also the expression of elevated levels of wild type αS can lead to degeneration of DA neurons.15,16 Mutations of the GBA gene (L444P and N370S), which causes Gaucher’s disease, a glycolipid storage disorder, has also been reported to induce the formation of Lewy bodies in the brain.17 Gaucher’s disease is an autosomal recessive disorder that primarily affects mononuclear phagocytes, which become engorged with stored lipids. In those who are heterozygous for a mutation in the GBA gene, there is an increased risk of developing PD. It has been postulated that these genetic mutations lead to enhanced protein aggregation or lysosmal dysfunction or a loss of function related to fluctuations in levels of ceramide causing PD.17 Mutations in another gene, LRRK2, are postulated to result in PD via a different mechanism. The LRRK2 gene (also known as PARK8) codes for dardarin, a protein with multiple functions including a leucine-rich region that likely is involved in protein−protein interactions and two distinct enzymatic domains; phosphorylation by a kinase domain and GTP-GDP hydrolysis by a ROC domain. LRKK2 is also involved in cellular functions such as neurite outgrowth, cytoskeletal maintenance, vesicle trafficking, autophagic protein degradation.18 Missense mutations of LRKK2 (R1441G, R1441C, N1437H, Y1699C, G2019S, and I2020T) lead to excitotoxicity due to increase in kinase activity. Of all the known missense mutations, G2019S is the most common.14 2.2. Mitochondrial Dysfunction and Oxidative Stress. Oligomeric αS aggregation within the mitochondria induces its fragmentation. This fragmentation may also be induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), rotenone, or oxidative stress. Fragmented mitochondria is a 45


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Figure 2. (a) Mitochondrial dysfunction in Parkinson’s disease: In the presence of MPTP, rotenone, or α-synuclein aggregates, mitochondrial fragmentation takes place. PINK1 and parkin are said have a role to play in this process. Mitophagy eliminates the damaged mitochondria. Ubiqitination of the outer membrane of the mitochondria leads to its degradation via the ubiquitin proteasome system (UPS). PINK1, PTENinduced putative kinase 1; drp-1, dynamin-1-like protein; miro: mitochondrial rho GTPase 1; mitofusin 1; MPTP, 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine; DJ-1, Parkinson disease protein 7, ROS: reactive oxygen species; LC3, microtubule-associated protein 1 light chain 3; UPS, ubiquitin proteasome system; LRRK2, leucine-rich repeat kinase 2; Atg7, autophagy-related protein 7.14,19−30 (b) Autophagy-lysosome system dysfunction in Parkinson’s disease. Autophagosomes remove damaged cellular components and deliver them to lysosomes having hydrolytic enzymes for degradation. Chaperone mediated autophagy degrade specific cytosolic proteins. α-SYN, α-synuclein; HSC70, heat shock cognate protein 70; LRRK2, leucine-rich repeat kinase 2; LAMP-2A, lysosome-associated membrane protein 2; GBA, glucocerebrosidase; GC: glucosylceramide; ROS, reactive oxygen species; BAX: Bcl-2-associated X protein; VPS35, vacuolar protein sorting-associated protein 35; ATP13A2, probable cation-transporting ATPase 13A2; MPP+, 1-methyl-4-phenylpyridine.31−43

specifically bind to lysosomal membranes through the LAMP 2A receptor. The number of autophagosomes are increased in the DA neurons of PD patients. Atg7 protein is the protein responsible for autophagosome formation and deletion of the Atg7 gene in DA neurons delay its degeneration. Atg7 dysfunction induces UPS for compensating the deficits of autophagy.35,36 There is an accumulation of LC3 (autophagosome inner membrane component), following loss of DJ-1.37 αS A53T mutation also induces neuronal death by promoting mitophagy.38 The LRRK2 protein maintains the acidic

damaged cellular components or organelles, wherein these autophagosomes engulf these materials prior to delivery to lysosomes containing a milieu of hydrolytic enzyme for degradation. CMA is involved in the degradation of specific soluble cytosolic proteins which contains motif recognized by the heat shock cognate protein 70 (HSC70).32 Substrates for CMA include wild type αS, while the process is inhibited by modified αS.32−34 Mutations in LRRK2 and αS alter the function of the lysosome-associated membrane protein type 2A (LAMP 2A) receptor, a CMA receptor. Substrate proteins 46


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Figure 3. Currently available treatment for PD. Levodopa is commonly used in PD. Along with it COMT, MAO-B, and DDC inhibitors are given in combination. Other drugs like dopamine agonist and anticholinergics are also administered. COMT, catechol-O-methyl transferase; MAO-B, monoamine oxidase B; DDC, dopa decarboxylase; LAT, L-amino acid transporter.44−51

environment within the lysosome and the autophagosome numbers. Following treatment with (1-methyl-4-phenylpyridinium) MPP+ release of lysosomal proteases are seen, which is inhibited by BCl2 associated X (BAX) and reactive oxygen species (ROS).24 Mutations within the genes for the endosomal/lysosomal proteins, GBA, vacuolar protein sorting-35 (VPS35) and type 5 P type ATPase ATP13A2 lead to PD. αS accumulation is seen in DA neurons deficient in VPS35, contained large endosome/lysosome and exhibited impaired retrieval of endosome to golgi LAMP-2 A CMA receptor.39,40 Functional ATP13A2 loss results in impaired catabolism of lysosome and αS accumulation.41 Glucosylceramide (GC) is degraded by lysosomes with the involvement of GBA and individuals carrying a single mutant allele of GBA are at higher PD risk.42 Although, PD patients have reduced GBA, irrespective of the patients harboring the mutation.43

proportion of levodopa to cross the blood brain barrier and exert its effects in the central nervous system. Levodopa is most effective in reducing the motor symptoms associated with PD patients; however, as the disease progresses, levodopa becomes effective for shorter and shorter periods. The reduction in levodopa efficacy is known as wearing off or the on−off phenomenon, in which duration of the clinical benefit with levodopa dose (on phase) becomes shorter. Other treatments, commonly used in conjunction with carbidopa and levodopa, can be helpful in maximizing the period during which rest tremor and rigidity are reduced. Inhibitors of catechol-O-methyl transferase (COMT) (Entacapone, Tolcapone) and inhibitors of monoamine oxidase B (MAO-B) (Selegiline, Rasagiline) serve to enhance the effect of levodopa by reducing its metabolism.45 However, as the disease progresses, the effectiveness of levodopa is reduced. In addition to delivering the precursor of dopamine to the brain, dopamine agonists are used to bind to DA receptors and minimize the motor symptoms of PD. Four dopamine agonists are used throughout the world; pergolide, bromocriptine, pramipexole and ropinirole. Pergolide and bromocriptine were developed first and have broader receptor activity than the newer agents. Pergolide is a D1 and D2 receptor agonist,46 while bromocriptine is an agonist with somewhat greater affinity for D2 receptors. Further, pergolide and bromocriptine both are ergot derived dopamine agonists reported to cause valvular heart disease through their action on 5-HT2B receptors

3. CURRENT AVAILABLE THERAPIES Levodopa is the first drug that was developed for PD and is used throughout the world.44 In the brain, levodopa crosses the blood-brain barrier (BBB) and is converted into dopamine by the cells of the SNpc. The SNpc cells then release dopamine, acting predominantly on striatal medium spiny neurons (Figure3). However, a relatively large quantity of levodopa is required to be administered in oral form, as it is rapidly metabolized in the periphery. To compensate, levodopa is administered along with carbidopa. Carbidopa inhibits the metabolism of levodopa in the periphery, allowing a greater 47


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ACS Chemical Neuroscience that are expressed on heart valves.47,48 The newer dopamine agonists, pramipexole and ropinirole, are more specific in their actions, and limited evidence indicates that their use may help to give patients a longer period of time before the wearing-off phenomenon begins.49,50 Likewise, other dopamine agonists like rotigotine, lisuride, and apomorphine with longer half-lives are used to provide continuous dopaminergic stimulation by altering the drug delivery system.51 Amantadine is an N-methyl-D-aspartate (NMDA) receptor antagonist which also acts by increasing dopamine release, having lesser side effects as compared to the above therapies. Parkinson patients may also be treated with anticholinergics (atropine, benztropine)for improved tremor control (Figure 3).10 Deep brain stimulation (DBS), a surgical technique was developed for PD and was approved as a therapy by the United States Food and Drug Administration in 2002.52,53 This involves the insertion of electrodes in either the subthalamic nucleus or the internal segment of the globus pallidus that delivers electrical stimuli to modify or interrupt the pattern of neural signaling. It is thought to act by inhibiting cells in the region surrounding the electrodes. However, the precise mechanism by which DBS exerts its effect is unknown. DBS improves the quality of life of PD patients by increasing the amount of time spent, each day, with better motor performance. Risks associated with the surgery may be infection and intracranial hemorrhage.53 Electromagnetic therapy (EMT) is an alternative, safe, and noninvasive approach for the management of PD.54 Transcranial magnetic stimulation (TMS), pulsed electromagnetic therapy (PEMT), repetitive transcranial magnetic stimulation (RTMS), and high frequency transcranial magnetic stimulation (HFTMS) are the different forms of EMT which have been employed for use for management of PD.54 These EMTs are said to show their effects by inducing changes within the brain network and positively affect the basal ganglia. Stimulation within the cortical region, mainly the prefrontal cortex and primary motor cortex, indirectly modulate the release of DA from the striatal neurons within the basal ganglia.55 This release of DA in turn brings about improvement in the motor symptoms of PD. EMT protocols can be molded as per the PD patient’s need. Various parameters are to be taken into consideration before designing an EMT protocol like the duration, frequency, stimulation intensity, pattern of stimulation, and so forth. EMT approach can be used solo or can be combined with any of the conventional treatment strategies to maintain the motor and nonmotor PD symptoms.54

to slow progression of PD. Potential novel therapies such asimmunization, stem cell implantation and other new targets for oral medication including NADPH oxidase, glutamate receptors, and serotonergic receptors may be beneficial. 4.1. Promoting Neuroprotection. Ca2+plays an important role in thesurvival of neuronal cells. Dysregulation in Ca2+ levels may lead to neurodegeneration. Reports suggests that an increase in brain Ca2+ levels promotes aggregation of αS.58 Hence, L-type calcium channel blockers such as isradipine, which decrease brain Ca2+ levels may promote neuroprotection in PD. A phase 3 study of the efficacy of isradipine in early PD is currently being conducted.59 Glucagon-like peptide 1 (GLP-1) may also be useful for PD patients. GLP-1suppresses microglial activation and inflammation, enhancing mitochondrial biogenesis and clearance of aggregated proteins.60,61 Geniposide, a GLP-1 analogue, increases the expression of insulin-degrading enzyme (IDE), a zinc-metalloendopeptidase that helps in degrading insulin and other small peptides that forms β-pleated sheets. IDE is activated by phosphoinositide 3-kinase (PI3K) and this inhibits αS fibril formation in vitro by binding to αS oligomers, blocking them from forming fibrils.60,62 Studies have shown that GLP-1 is secreted in the brain which acts on GLP-1 receptors. GLP-1 agonist exendin-4 (exenatide) and its different synthetic analogs have been used in PD as they are resistant to dipeptidyl peptidase IV (DPPIV) action which is responsible for metabolizing endogenous GLP-1.61,63 Results have also shown that these drugs restored the levels of dopamine and improved motor function in vivo. The potential neuroprotective effects of exendin-4, a GLP-1 agonist, havebeen associated with modifications in intracellular calcium levels and an increase in Mfn2. Mfn2 enhances endoplasmic reticulum−mitochondria coupling, as the accumulation of αS causes mitochondrial fragmentation and/or damage by reducing this ER−mitochondrial connectivity.64 Exendin-4 prevents microglia activation, suppresses proinflammatory cytokine production and also restores dopamine and tyrosine hydroxylase (TH) activity in lipopolysaccharide (LPS) and MPTP-induced PD models.65,66 Exendin-4 and has been approved for phase 3 clinical trials.67,68 A transcription factor nuclear factor (NF)-κB, involved in PD pathogenesis is inhibited by Exendin-4, reducing neuroinflammation and improving cell viability.69 Recently, it has been proved that exendin-4 shows positive effects on PD patients in clinical trial but the underlying mechanism is still unknown.70 Similar to exendin-4, liraglutide and lixisenatide are the GLP-1 agonists with longer biological half-life were tested in preclinical model of PD and both the drugs have shown neuroprotective effect superior to the exendin-4.71 Niacin, a precursor of nicotinamide adenine dinucleotide (NADH), and nicotinamide adenine dinucleotide phosphate (NADPH) are required for dopamine synthesis72 which are usually depleted in PD due to the administration of levodopa. GPR109A (niacin receptor agonists) has demonstrated antiinflammatory action via (NF)-κB, hence, may protect DA neurons from damage and prevent disease progression.72,73 It has been shown that activation of peroxisome proliferatoractivated receptor-γ (PPARγ), a member of the nuclear receptor superfamily, reduces inflammatory responses in vitro and in vivo by protecting cells from death and toxicity.74 It plays a role in lipid homeostasis, glucose metabolism, inflammation, cellular differentiation, and proliferation.

4. NOVEL THERAPEUTIC STRATEGIES TO TREAT PARKINSON’S DISEASE To gain deeper knowledge about the disease a number of experimental models have been developed to genetically or chemically induce PD. Chemical agents, used to recapitulate some of the features of PD in animals, include MPTP, 6hydroxydopamine (6-OHDA), rotenone, and paraquat.56 However, none of the available models are able to replicate the full spectrum of physical symptoms and neuropathology found in humans.57 Thus, animal models of PD are of limited utility in the development of novel therapeutics. The current treatments provide only symptomatic relief with numerous side effects. There is no treatment available that halts or slows the progression of disease. Hence, it is important to identify new targets with lesser side effects and the potential 48


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and in disaggregating its oligomers.98 Polyphenols convert insoluble oligomers into a soluble form, thereby decreasing neurotoxicity.99 Polyphenols like baicalein, scutellarin, myricetin, epigallocatechin gallate (EGCG), nordihydroguaiaretic acid (NDGA), and black tea extract have shown promising results and may prove to be potential drug molecules in the future to inhibit and disaggregate αS which can help to treat PD.7 Another potential method of clearing the brain of αS aggregates is via the use of specific antibodies. Single chain fragment variable antibodies (ScFvs) are new agents for therapy of PD. These consist of minimal antigen binding site, the VH and VL variable domains, linked by a flexible polypeptide linker and can be used against misfolded αS proteins.45,100 These antibodies can be expressed using bacterial and mammalian gene expression system, intracellularly as well as through therapeutic gene delivery.101 The best part about ScFvs is their specificity as they go and bind specifically only to DA-modified proteins which are important in the case of PD as αS misfolding is directly involved in dopamine synthesis.45 A genetic mutation in LRRK2 gene leads to increase in kinase activity responsible for PD.102 To date, an endogenous ligand for LRRK2 kinase inhibitor is not known, but it may be considered as a good target for neuroprotective therapy.103 Henderson et al.104 and Daher et al.105 evaluated the effect of LRRK2 kinase inhibitor PF-06447475 in vivo, and they obtained promising results.104 This molecule has been reported to block As toxicity probably by modulating neuroinflammatory processes that are responsible to cause dopaminergic neuronal degeneration.105 Hence, LRRK2 kinase is a good target and need to be explored. Mitochondrial transcription factor A (TFAM), a mitochondrial protein, plays a role in mitochondrial DNA (mtDNA) transcription and mtDNA maintenance. Mutation in mtDNA has been found to be involved in PD pathogenesis. Currently, limited supportive data is available but it canprove to be a future potential target for PD.87,106 4.3. Strategy for Neuronal Regeneration. Reports suggest that levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) are decreased in PD.107 These agents help in the growth of DA neurons and is neuroprotective in nature. GDNF has been used to regenerate TH positive nigral neurons in vivo.108 There was an improvement in motor functions seen as a result of increased dopamine levels. But the study failed to produce similar results in clinical trials.109 Neurturin, a GDNF analogue has proved to be effective in animal models and is currently in clinical trials.103,110 In vitro and in vivo experiments have shown that erythropoietin (EPO) can act as an antioxidant, promote maturation of DA neurons, increase the level of dopamine and show anti-inflammatory activity.111 So, EPO receptor agonist can prove beneficial for PD. Eltrombopag has shown very good activity in both in vitro and in vivo.96 Clinical trials for antioxidants like vitamin E and MAO-B inhibitors (selegiline) were conducted, but the results were not satisfactory.112 Vitamin E conferred limited neuroprotection, while selegiline exhibited neuroprotective action by a mechanism different from that of MAO-B inhibition. It acts through stimulation of neurotrophic factor synthesis and induction of superoxide dismutase.113 Also, coenzyme Q10, a

PPARγ agonists have shown neuroprotective effects in many neurodegenerative diseases like PD in C57BL/6 mice, alzheimer’s disease in APPV717I mice75 and ischemia in wistar rats.76 Pioglitazone, a PPARγ agonist, protects DA neurons from degeneration, inhibits microglial activation and monoamine oxidase (MAO) enzyme activity in the striatum of rodent models of PD.74,77 It also increases neuronal glucose uptake and restores ATP levels in the brain.78 PPARγ also has a role protecting mitochondrial function. It helps to maintain mitochondrial membrane potential by providing mitochondria with alternative substrates for coupled electron transport and oxidative phosphorylation.79,80Pioglitazone stabilizes MitoNEET, an iron−sulfur containing outer mitochondrial membrane protein which regulates oxidative capacity.81Despite promising results in mouse and monkey models, it failed in phase 2 clinical trials.74,82,83 A possible explanation for the negative outcome is that toxin animal models are not reflective of PD pathogenesis. Another possibility is that pioglitazone failed to reach the target nigral neurons in a high enough concentration.82 Another PPARγ agonist, rosiglitazone, also shows similar action, thus inhibiting neurodegeneration.84 PPARγ Coativator-1α (PGC-1α) is important in driving and coordinating mitochondrial biogenesis and respiration, oxidative phosphorylation, gluconeogenesis, glucose transport, glycogenolysis, peroxisomal remodeling, fatty acid oxidation, and muscle fiber-type switching.85 In PD, it shows neuroprotective activity by increasing the levels of ROS-detoxifying enzymes, such as superoxide dismutase (SOD) 1 and 2, catalase and glutathione peroxidase and has also been proved in vivo.80 During aging, it is observed that levels of PGC-1α are decreased due to reduction in the levels of sirtuin1.86 Hence, experiments have been carried out by overexpressing PGC-1α in vitro and it has shown to protect cells by increasing the levels of antioxidants. In vivo, it protects DA neurons by inhibiting mitochondrial dysfunction.87,88 Nuclear receptor-related 1 (Nurr1), is a nuclear receptor involved in both the biosynthesis of dopamine and the survival of DA neurons.89 Nurr1 has been shown to enhance in vitro and in vivo transcription of TH which is the rate-limiting enzyme of dopamine biosynthesis, and of GTP cyclohydrolase I (GCH1), the first enzyme in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for TH activity.90,91 Decreased Nurr1 levels have been strongly associated with PD and reduced DA neuron survival.92 Nurr1 binds to DNA as a monomer, homodimer, or heterodimer with retinoid X receptor (RXR)α or RXRγ. Because Nurr1 heterodimerizes with RXRα in midbrain DA neurons, Spathis et al.93 have designed Nurr1:RXRα-selective lead molecule which has been proven to prevent DA neuronal loss and striatal DA denervation in vivo.93 4.2. Disease Modification by Targeting Mutated Genes. The microtubule system (MT) is involved in mitosis.94 It has been reported that microtubule dysfunction takes place due to environmental toxins and is responsible for the formation of αS in animals.95 Hence, microtubule stabilizing agents (Cevipabulin, Cyclostreptin, Laulimalide, Peloruside, Taccalonolide) are potential agents in thetreatment of PD.96,97 As discussed, distinct genetic mutations have been identified in theαS gene at A53T, A30P, and E46K sites in rare cases of familial PD. Polyphenols are available in many natural compounds and have shown positive effects in inhibiting αS 49


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NGF, insulin-like growth factor 1 (IGF-1), transforming growth factor alpha (TGF-α), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF).124,125 These growth factors lead to increase in TH gene expression and dopamine content both in vitro and in vivo.126 An important advantage with MSCs are that they are immunoprivileged and have no ethical concerns for its use.127 Also, MSCs in the subventricular zone (SVZ) leads to a proliferation of endogeneous progenitors, and they also have anti-inflammatory and immunomodulatory activities. Another mechanism for protection of DA neurons is the recovery of BBB, which is compromised in PD.124 Human adipose-derived stem cells (hASCs), a type of MSCs, can differentiate into neuronal cells and increase dopamine levels along with the recovery of DA neurons due to improvement in mitochondrial function in vivo.125 Neural stem cells (NSC) and progenitor cells present in the SVZ are responsible for constitutive neurogenesis. Dopamine levels are brought to normal by stimulating NSC which can travel to the striatum and gets differentiated into DA neurons and can decrease the motor symptoms of PD.128 Results have shown that progenitor cells can produce new neurons in vitro but not in vivo. There is an increase in DA neurons in rodents, in primates, and also in PD patients who have been tested by measuring the presence of TH-positive cells. TGF-α and exendin-4 have shown promising effects on proliferation of progenitor cells in vitro. There has been an increase seen in a number of neuroblasts in SVZ and striatum using a combination of EGF and FGF-2 treatment in 6-OHDA treated rats.125 Zuo et al.129 carried out studies to test the therapeutic efficacy of NSCs in 6-OHDA model of PD.129 NSCs showed improvement in motor and cognitive activities as compared to lesion control animals. This behavioral improvement was seen due to alterations in the proteome profile, neurotrophic factor secretion and cytokine levels in the SVZ and functional improvements was due to stimulation of neurogenesis in SVZ through the resident stem cells within this niche that initiated a multifaceted brain regenerative machinery.129,130 Altarche-Xifro et al.131 carried out experiments to show that hematopoietic stem and progenitor cells (HSPCs) can fuse with neurons and glial cells in vivo, and get converted to mature astroglia releasing neurotrophic factors and wnt1 which prevents the secretion of proinflammatory cytokines.131 These factors decrease DA neuronal degeneration but do not help in regenerating new DA neurons. The major disadvantage of HSPCs is that following 1 week of transplantation there is immune rejection, leading to a decrease in the number of cells.131 There are challenges with the use of stem cells that vary from the choice of cells to the number of cells used for transplantation and timing of delivery. Other challenges include dissecting the mechanisms by which these cells work, their possible side effects, and their immune rejection in the host body.122 As per reports available on clinicaltrials.gov, 20 trials have been reported wherein stem cells have been transplanted in PD patients, of which 14 are active, the status of 2 are unknown, and 2 have been either terminated or suspended. Only 1 of the listed trials has been completed; however, the results are yet to be published. The first clinical trials with stem cells in PD patients was reported in 1987, where human fetal mesencephalic tissue rich in dopaminergic neuroblasts was transplanted intrastriatally to see whether the transplanted cells could survive and re-establish functional connections in the

cofactor involved in electron transport chain in mitochondria, has shown a positive neuroprotective effect in rodent modelsbut has failed to show clinical benefits.103,114 4.4. Immunization. Immunization may be a successful therapy for preventing PD.115 It has been shown that mice with fewer T cells have greater neuronal loss.116 Theoretically, one can say that self-antigen-stimulated T lymphocytes enter the damaged nigrostriatal tissues and generate both neurotrophins and neurotrophic factors.117 To prove this, Benner et al.118 vaccinated MPTP intoxicated mice with copolymer-1 (Cop-1; Copaxone, glatiramer acetate), a random amino acid polymer that generates nonencephalitic T cells used to treat relapsingremitting multiple sclerosis.118,119 They showed that Cop-1 immunized cells are transferred to damaged brain regions, where they decreased microglial response and increased GDNF. Results have shown that there is also an increase in SNpc TH neuronal bodies and striatal fibers. Also, it has shown to generate TH1, TH2, or TH3 which suppresses innate immunity by decreasing the production of cytokines and generates neurotrophic factor receptors, tropomyosin receptor kinase B (trkB), and tropomyosin receptor kinase C (trkC). Thus, vaccination strategy could prove successful in providing neuroprotection by protecting DA neurons in PD.118 Bacillus Calmette-Guerin (BCG) vaccine (containing live attenuated Mycobacterium bovis) can also be used for the treatment of PD. Experiments have shown that complete Freund’s adjuvant (CFA) (containing inactivated Mycobacterium tuberculosis in mineral oil) showed more immune stimulation rather than TH and Copaxone in CFA. But CFA is unsuitable for human use. Hence, experiments were carried out to check whether BCG can be used as a neuroprotective vaccine to prevent neurodegeneration.120 Results have shown that there is an increase in dopamine transporters and dopamine levels in MPTP mouse model along with activation of Th1-type CD4+ T cells which is known to antagonize the development of Th17 cells and induce apoptosis of selfreactive T cells, thus providing neuroprotection. BCG also activates antigen presenting cells (APCs) and induces the production of regulatory T cells (Tregs) which causes a decrease in inflammatory response. Another mechanism for neuroprotection is believed to be the diversion of the T effectors and macrophages to the periphery and avoiding their entrance to CNS. From the entire study, authors concluded that BCG vaccination is a safe treatment for preventing DA neuronal loss and providing neuroprotective effect.121 4.5. Stem Cell Therapy. Stem cells can differentiate into neurons, astrocytes, and oligodendrocytes, and after transplantation they can move to and generate neurons at the site of injury. Apart from regeneration of neurons, other mechanisms of protection by stem cells include neuromodulatory and neuroprotective effects that are exhibited by the cells themselves or by their secretions.122 Induced pluripotent stem cells (iPSCs) are converted into neural precursor cells which are further differentiated into neurons and glial cells, thus improving behavior and motor function in vivo.123 These cells can also be differentiated into DA neurons in vitro. Along with these iPSCs, mesenchymal stem cells (MSCs), also called as “marrow stromal cells,” stimulate regeneration by promoting endogenous neurogenesis and protect DA neurons by secretion of cytokines and nerve growth factors from cells that create an environment favorable for neuroregeneration when supplied with growth factors like BDNF, fibroblast growth factor 2 (FGF-2), epidermal growth factor (EGF), 50


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ACS Chemical Neuroscience Table 1. Various Approaches Involved in the Management of PDa sl. no.

approach

ref

neuroprotection 1 2 3 4 5 6 7 1 2 3 4 1 2 3 4 1 2 1 2 3 4 5 6 1 2 3 4 1 2 3 4 5 6 7

L-type calcium channel blockers (isradipine) GLP-1 analogue (geniposide) GLP-1 agonists (exenatide, liraglutide, lixisenatide) niacin receptor agonists (GPR109A) PPARγ agonists (pioglitazone, rosiglitazone) PGC-1α activators Nurr1:RXRα agonist

58, 60, 61, 72, 74, 85 93

targeting mutated genes microtubule stabilizing agents (cevipabulin, cyclostreptin, laulimalide, peloruside, taccalonolide) polyphenols (baicalein, scutellarin, myricetin, EGCG, NDGA, and black tea extract) specific antibodies (ScFvs) LRRK2 kinase inhibitor (PF-06447475) neuronal regeneration tropic factors (BDNF, GDNF, NGF) GDNF analogue (neurturin) erythropoietin analogue (eltrombopag) antioxidants (Vit E, CoQ10) immunization Cop-1 immunized cells BCG vaccine stem cells iPSCs MSCs hASCs NSCs NPCs HSPCs targeting neuroinflammation PLA2 inhibitors superoxide release inhibitors (sinomenine, squamosamide derivative, sinomenine, squamosamide derivative, TGF-b1, verapamil, and resveratrol) NSAIDS (COX inhibitors) glucocorticoids others 5HT1A receptor agonist (Sarizotan HC1) A2a antagonist (caffeine) GAPDH inhibitors (propargylamine, TCH346 and CEP-1347) NMDA receptor antagonists AMPA receptor antagonists (NBQX, GYKI 52466 and Talampanel) DBS EMT

59 62 63, 71 73 77, 78, 84

96, 97 7, 98 45 104, 105 107 103, 110 96 112, 114 118 121 123 124, 126 125 125, 129 128 131 139 138 140, 141 142 145 146 101, 108 108, 150 151, 152 53 54

a

GLP-1, glucagon-like peptide-2; PPAR, peroxisome proliferator-activated receptor; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; EGCG, epigallocatechin gallate; NDGA, nordihydroguaiaretic acid; ScFvs, single-chain variable fragment; LRRK2, leucine-rich repeat kinase 2; BDNF, brain-derived neurotrophic factor; GDNF, glial cell-derived neurotrophic factor; NGF, nerve growth factor; CoQ10, coenzyme Q10; Cop-1, copaxone, glatiramer acetate; HSPCs, hematopoietic stem and progenitor cells; PLA2, phospholipase A2; TGF-β1, transforming growth factor beta 1; 5HT1A, serotonin 1A receptor; A2a, adenosine receptor 2a; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DBS, deep brain stimulation; EMT, electromagnetic therapy.

diseased area. Beneficial results were obtained as compared to the sham controls; however, uncontrollable dyskinesias were reported in few patients.132 A controlled, double blind trial with bilateral fetal nigral transplantation was carried out by Olanow et al. No overall beneficial effect was seen and over 50 six percent of the patients developed dyskinesia.133 In a prospective, uncontrolled trial carried out by Venkataramana et al., autologous bone marrow derived MSCs were transplanted. Subjective improvement in symptoms were reported and no serious adverse effects were observed following stem cell transplantation. Although the effectiveness of the treatment could not be assessed due to the uncontrolled nature of the trial. However, results from this trial support and encourage future trials with larger patient number to establish efficacy.134

Table 2 lists all major clinical trials investigating different stem cells for PD. 4.6. Targeting Neuroinflammation. As mentioned earlier, oxidative stress plays an important role in the pathogenesis of PD leading to loss of DA neurons.135 NADPH oxidase (PHOX) is a superoxide-producing and enzyme complex in phagocytes playing an important role as a defense mechanism.136 As a result of ROS production, NADPH oxidase is activated and it takes part in host defense, cellular signaling, stress response, and tissue homeostasis. The overactivity of NOX2 (a subunit of NADPH which is present in phagocyte) increases ROS production from activated microglia leading to oxidative stress due to neuroinflammation and chronic neurodegeneration. Microglial activation releases 51


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ACS Chemical Neuroscience Table 2. Clinical Trials Investigating Different Types of Stem Cell as a Potential Therapy for PDa sl. no.

trial ID

country

intervention

status

outcome measures

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

NCT00976430 NCT03128450 NCT03550183 NCT01446614 NCT02780895 NCT02611167 NCT01329926 NCT03309514 NCT02538315 NCT01453803 NCT02452723 NCT03119636 NCT02184546 NCT00927108 NCT02511015 NCT02795052 NCT03297177 NCT00874783 NCT01953523

India China China China Mexico United States Unites States N/A Canada United States Australia China United States Thailand United States United States and United Arab Emrates United States Israel United States

BM-MSCs NSCs MSCs BM-MSCs SCs allogeneic BM-MSCs NSCs N/A N/A AD-SVF NSCs ESC-NPCs AD-SCs NSCs N/A BM-MSCs SCs iPSCs AD-SVF

suspended enrolling recruiting unknown active recruiting enrolling not yet recruiting recruiting withdrawn recruiting recruiting active unknown completed recruiting recruiting recruiting unknown

safety and efficacy safety and efficacy safety and efficacy safety and efficacy N/A safety, feasibility, and efficacy N/A safety and efficacy N/A safety and efficacy safety safety and efficacy N/A N/A N/A Efficacy safety and efficacy N/A safety and clinical outcomes

a

SCs, stem cells; MSCs, mesenchymal stem cells; NSCs, neural stem cells; BM, bone marrow; AD, adipose derived; iPSCs, induced pluripotent stem cells; SVF, stromal vascular fraction; ESC, embryonic stem cells; NPC, neural progeneitor cells.

are decreased in such patients. Hence, inhibitors of phosphodiesterase 7 which is expressed in brain can prove effective by increasing the cAMP levels due to the reduction of hydrolysis.96,144 Serotonergic receptors (5-HT1A, 5-HT1B, 5-HT2A, and 5HT2C) play an important role in PD as they are involved in levodopa induced dyskinesia (LID). It has been proven in clinical trials that 5HT1A receptor agonist sarizotan HC1 can help in treating LID.145 Caffeine, an adenosine receptor (A2a) antagonist, has shown good results in PD patients.146 A2a receptor heterodimerizes with the D2 receptor present in the brain which inhibits signaling of dopamine. Hence, Adenosine receptor antagonist can be targeted for PD.103,147 Also, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme which plays a role in initiating apoptosis. Propargylamine TCH346 and CEP-1347, GAPDH inhibitors has shown good results in vivo for PD but have failed in clinical trials.103,110 Glutamate, which binds to NMDA receptors on DA neurons, plays a role in excitotoxicity in PD. Activation of NMDA receptors causes an influx and increase in intracellular calcium levels which, when uncontrolled, lead to cell death.148 Hence, NMDA receptor antagonists are potential therapeutic agents.103,110,149,150 α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors also increase glutaminergic transmission. So, likewise, the use of AMPA receptor antagonists like 2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) and GYKI 52466 can also inhibit excitotoxicity; however, they failed to inhibit motor symptoms. Talampanel has successfully passed phase 2 clinical trials.151 More molecules are needed to be developed for this potential target.152

cytokines, chemokines, eicosanoids, and ROS, of which NOX2 derived ROS, which is increased due to aggregation of αS, plays a role in DA neurodegeneration.137 Hydrogen peroxide and peroxy nitrite from activated microglial NOX2 enters neurons and disrupts mitochondrial function by decreasing ATP production and increasing ROS. Hence, there is a need to inhibit NOX2 to protect DA neurons from degeneration. Drugs like sinomenine, squamosamide derivative FLZ, pituitary adenylate cyclase-activating polypeptides, transforming growth factor-b1 (TGF-b1), verapamil, and resveratrol. All these drugs inhibited superoxide release from microglia in vitro.138 Neuroinflammation and neural damage may also result from increased phospholipase A2 (PLA2) activity, due to increase in fatty acids and lysophospholipid contents, which eventually develop into secondary messengers after a series of metabolic steps. Many PLA2 inhibitors have been studied in rat models of PD and have shown very potent activity against PD.96,139 Nonsteroidal anti-inflammatory drugs (NSAIDS) reduce the activity of cyclooxygenase (COX), thus decreasing prostaglandin and inhibiting ROS and RNS generation.140 It also activates PPARγ which, as mentioned above, have antiinflammatory properties. There are many evidence which point out the neuroprotective effects of NSAIDS and can protect DA neurons from degeneration.141 Apart from these, glucocorticoids are also usedagainst neuroinflammation as their receptors are present on microglia which activate (NF)-κB, responsible for inflammation.142 4.7. Other Targets. A few novel targets have also been identified for therapy of PD (Table 1). One such target is the angiotensin-2 peptide that activates angiotensin-1 receptor, increasing the formation of NADPH and superoxide leading to microglial activation. Thus, angiotensin is found to be involved in dopamine neuronal degeneration in substantia nigra, caudate nucleus. Hence, angiotensin-converting enzymes (ACE) inhibitors like perindopril have proved to be beneficial to treat PD.96,143 Experiments have found the involvement of cyclic adenosine monophosphate (cAMP) in PD, whose levels

5. CONCLUSION Current therapies for PD focus more on providing symptomatic relief, rather than providing a means by which it can target the main pathology of the disease. Many advances have been made in PD therapy as discussed. Of the newer 52


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approaches, therapy based on stem cells may be promising. The majority of the questions that arise at clinics may not be solely answered by preclinical studies; hence, further well designed clinical studies are warranted to validate their efficacy and safety. Researchers should also explore utilizing combination therapies rather than focusing on single therapy to treat PD patients for a better outcome.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; pallab.bhattacharya@ niperahm.ac.in. ORCID

Pallab Bhattacharya: 0000-0003-2867-1650 Author Contributions

N.S. and P.B. have equal seniority in this study. P.R., D.S., S.B., A.G., A.B., N.S., K.R.D., and P.B. conceived and designed the study. P.R., D.S., N.S., and P.B. outlined the performed rigorous literature search. N.S., A.B., K.K., and P.B. conceived and designed the figures and images. P.R., D.S., A.G., K.R.D., N.S., and P.B. wrote the manuscript. P.R., D.S., H.K., and P.B. worked on the rebuttal and addition of new sections. Funding

This work is supported by the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India and National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, India. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The authors also want to express their thanks to the Director, NIPER Ahmedabad for providing necessary facilities and infrastructure.

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Novel Targets for Parkinson's Disease: Addressing Different

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