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| REVIEW ARTICLES |
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| Year : 2021 | Volume
: 4
| Issue : 3 | Page : 99-110 |
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Neuroprotective strategies in Parkinson’s disease: A long road ahead
Divyani Garg1, Soaham Desai2
1 Department of Neurology, Neo Hospital, Noida, Uttar Pradesh, India
2 Department of Neurology, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Anand, Gujarat, India
| Date of Submission | 23-Aug-2021 |
| Date of Decision | 05-Sep-2021 |
| Date of Acceptance | 28-Oct-2021 |
| Date of Web Publication | 22-Dec-2021 |
Correspondence Address:
Dr. Soaham Desai
Consultant Neurologist and Head, Department of Neurology, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Karamsad, Anand - 388 325, Gujarat.
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/AOMD.AOMD_38_21
Neuroprotection has been a fascinating area of research in Parkinson’s disease (PD). It offers the promise of disease modification, in turn, slowing the disease progression. A vast array of agents has been assessed for its neuroprotective properties. Although many of these agents have achieved varying degrees of efficacy in preclinical models of PD, definitive success has not been observed in clinical trials. The reasons underlying the lack of success lie within the intrinsic heterogeneity of PD. Instead of using a single agent for all patients in a “one-size-fits-all” approach, it is increasingly apparent that a specific study population with a well-defined predominant pathogenic mechanism should be selected for trials, assessing the role of each agent targeting a specific mechanism. Coenzyme Q10 may find use in an enriched cohort of PD patients with PARKIN mutations. The glucagon-like peptide 1 (GLP-1) analogue, exenatide, is currently being assessed in a phase III trial. Other GLP-1 agonists, such as liraglutide, lixisenatide, and semaglutide, are undergoing phase II trials. In addition, coffee has been shown to have a nonlinear relationship with PD risk. With increasing genetic and molecular understanding of PD, the dream of neuroprotection in PD may be realized in the near future. In this review, we summarize the current evidence on neuroprotection in PD. Keywords: Caffeine, dopamine agonists, immunotherapy, levodopa, neuroprotection, nicotine, Parkinson’s disease
How to cite this article:
Garg D, Desai S. Neuroprotective strategies in Parkinson’s disease: A long road ahead. Ann Mov Disord 2021;4:99-110 |
How to cite this URL:
Garg D, Desai S. Neuroprotective strategies in Parkinson’s disease: A long road ahead. Ann Mov Disord [serial online] 2021 [cited 2023 May 29];4:99-110. Available from: https://www.aomd.in/text.asp?2021/4/3/99/333363 |
| Introduction | |  |
The global burden of Parkinson’s Disease (PD) has increased to above six million people, from 1990 to 2016.[1] This is projected to increase to 10 million by 2030. It is the fastest growing neurological disorder worldwide, leading to substantial disability and economic burden.[2],[3] As per the global disease survey in 2021, an estimated 7, 71, 000 people in India had PD, and 45,300 deaths.[4]
PD is characterized by heterogeneous symptoms.[5] The diverse and progressive nature of symptoms places considerable burden on both patient and caregiver.[6],[7] In addition, quality of life is considerably impacted.[8],[9] To date, levodopa remains the therapeutic gold standard. Nearly 40–60% of cell loss in the substantia nigra pars compacta and 60–70% of striatal dopamine depletion must occur for motor symptoms to become evident. Therefore, there is a wide window of opportunity for neuroprotection in PD, considering that the prodromal phase may last from 5-20 years.[10] Neuroprotective strategies, probably the greatest unmet need in PD therapy, include: (i) buffeting compensatory mechanisms, (ii) salvaging dying neurons or “neurorescue,” and (iii) replacing degenerating neurons via cell-based therapy or neurorestoration. Although several putative agents have been investigated, none have yielded significant promise.[11],[12],[13]
In this review, we provide an updated summary of the underlying pathophysiological mechanisms of PD that may be targets of neuroprotection, advancements in neuroprotective strategies, molecules in the pipeline, reasons for the lack of success, thus far, and possible future strategies to triumph in neuroprotection trials.
| Search Methodology | | |
We performed an electronic search using the PubMed database to include articles from January 1990 up to July 2021 on July 31 2021. The following keywords were used: “neuroprotection” OR “neuroprotective strategies” OR “neuroprotective” OR “disease modification” OR “disease modifying,” and “Adenosine 2A” OR “Amantadine” OR “Caffeine” OR “Coenzyme Q10” OR “Creatine” OR “Deprenyl” OR “Diet” OR “Exenatide” OR “Exercise” OR “Glucocerebrosidase” OR “Immunotherapy” OR “Inosine” OR “Iron chelators” OR “Isradipine” OR “Levodopa” OR “neurotrophic factor” OR “Rasagiline” OR “Safinamide” OR “Selegiline” OR “Ropinirole” OR “Nicotine,” and “Parkinson’s disease.” In addition, cross-references, if relevant, were included. The search conducted on August 20, 2021, yielded 1341 results. After removing duplicates and irrelevant studies, 844 studies remained. The titles and abstracts of these remaining studies were screened by two reviewers (DG, SD). We excluded articles in non-English languages and those with only abstracts or conference presentations, and the full text of 257 articles was accessed and reviewed in detail. After excluding articles with incomplete details or contentious or analogous descriptions, 92 articles were finally included in this review ([Figure 1]).
| Pathophysiological Mechanisms of PD: Potential Targets for Neuroprotection | | |
Multiple pathophysiological mechanisms underlying PD have been targeted for neuroprotection ([Figure 2]).[11],[12],[13] The 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) animal models are insufficient to holistically explain PD pathophysiology. | Figure 2: Pathogenesis of Parkinson’s disease and targets for neuroprotection
Click here to view |
| Precision-Based Approach | | |
a) Organelle-specific
- Mitochondrial dysfunction: Mitochondrial dysfunction is known to occur in sporadic PD. Intramitochondrial α-synuclein aggregation causes cellular injury and demise.[14]
- Lysosomal dysfunction: It is important in GBA gene mutation-associated PD, which encodes β-glucocerebrosidase enzyme. This leads to altered glycosphingolipid homeostasis, synaptic vesicular trafficking disruption, and enhanced α-synuclein aggregation.[15]
b) Protein-specific
- β-glucocerebrosidase: Genetic mutations in GBA gene lead to both Gaucher’s disease and PD. Mutated β-glucocerebrosidase accumulates in the endoplasmic reticulum (ER), leading to lysosomal dysfunction, and α-synuclein aggregation.
- LRRK2: Toxic gain-of-function mutations in the LRRK2 gene lead to autosomal dominant PD.[16]
| Broad-Based Approach | | |
Oxidative stress
Mitochondrial-specific dysfunction and mutations are known to occur in the PD brain.[17] The mitochondrial complex I is primarily responsible for producing reactive oxygen species (ROS) which induces apoptosis in dopaminergic neurons.[18]
Neuroinflammation
Neuroinflammatory mechanisms contribute towards development of PD. α-synuclein aggregation is associated with inflammation.[19]
Monoamine oxidase B activity
This evidence is derived from the MPTP model. MPTP is converted to N-methyl-4-phenylpyridinium (MPP+) by MAO-B in the astrocytes. MPP+ enters dopaminergic neurons where it inhibits mitochondrial oxidative phosphorylation, creating ROS and cellular damage.[20]
Calcium dyshomeostasis
Cells in the substantia nigra pars compacta have pacemaking properties. Calcium entry via the L-type calcium channels, Cav.1.3 channels, drive mitochondrial oxidative phosphorylation, leading to oxidative stress.[21]
Apoptosis
Upregulation of apoptotic pathway proteins is reported in PD.[22]
Endoplasmic reticulum trafficking
ER is a key cell organelle mediating protein homeostasis. In PD, α-synuclein aggregates stress the ER, disrupting synaptic vesicle, intracellular protein trafficking and calcium equilibrium.[23]
Iron accumulation
Iron overload in the substantia nigra is implicated in PD pathogenesis,[24] and fuels oxidative stress and dopaminergic cellular injury.
Toxic oligomer formation
α-synuclein aggregation leads to multipronged intracellular dysfunction involving mitochondrial, lysosomal, and protein transport processes.[25] However, whether these aggregates are pathogenic or only an epiphenomenon of the upstream processes (considering their universality in PD patients), is debatable.[26]
Glutamate-mediated toxicity
Impairment of glutamate homeostasis may induce death of dopaminergic neurons, observed in both acute and genetic animal PD models.[27]
| Neuroprotective Agents | | |
An array of agents has been assessed for neuroprotective properties in PD. We have summarized the evidence below. [Table 1]
Levodopa
The dopamine precursor, levodopa, remains the gold standard of PD treatment. In addition to its diverse motor and non-motor effects, neuroprotection has been predicted as a potential benefit.
Earlier versus Later L-DOPA (ELLDOPA) Study
Published in 2004, this study suggested that levodopa therapy either slowed progression of PD or had prolonged symptomatic benefits. Patients with early PD received levodopa and placebo for 40 weeks. Patients who received levodopa did not deteriorate to the same extent as placebo, suggesting neuroprotection or a sustained effect. However, neuroimaging data showed potential acceleration of loss of dopaminergic nerve terminals or modified dopaminergic transporter in the striatum in the early PD group.[28]
Levodopa in Early Parkinson’s disease (LEAP) Study
This was a multicenter randomized clinical trial in the Netherlands, in which 445 patients with early PD were randomized to receive levodopa with carbidopa for 80 weeks (early-start group, 222) and 40 weeks (delayed-start group, 223).[29] The early-start group was exposed to a longer duration of the potential neuroprotective effects of levodopa. The total Unified Parkinson’s Disease Rating Scale (UPDRS) score change from baseline to week 80 was -1.0 point in the early-start group compared to -2.0 points in the delayed-start group (95% Confidence Index: -1.5–-3.5; p = -0.44), suggesting the lack of neuroprotective effects of levodopa, despite longer exposure in the early start group.
MAO-B inhibitors
Selegiline
Selegiline demonstrates dopamine-sparing properties due to MAO-B inhibition. In addition, it has oxidative, antiapoptotic, and neuroprotective properties, attributable to its propargylamine moiety.
Deprenyl and Tocopherol Antioxidant Therapy in PD study
This multicenter clinical trial studied the effect of deprenyl (selegiline) and tocopherol in early PD.[30] Eight hundred participants were randomly assigned to one of the four groups: placebo, active deprenyl (5 mg twice daily) with placebo tocopherol, active tocopherol (2000 IU) with placebo deprenyl, and both active drugs. Deprenyl, but not tocopherol, was found to delay onset of levodopa therapy. However, it remained unclear whether this was due to its neuroprotective effect or beneficial symptomatic effect.
Sinemet–Depreneyl–Parlodel study
This randomized trial aimed at assessing the effect of deprenyl and levodopa–carbidopa (Sinemet) in early PD.[31] Hundred participants were randomized into one of four groups: deprenyl with Sinemet, deprenyl placebo with active Sinement, deprenyl with bromocriptine, and deprenyl placebo with bromocriptine. Change in the UPDRS score from baseline to follow-up at 14 months (primary outcome), 2 months after withdrawal of deprenyl or placebo, and 7 days after withdrawal of Sinement of bromocriptine was noted. Less deterioration was observed in deprenyl-treated patients (0.4 ± 1.3 points) than placebo-treated patients (5.8 ± 1.4 points) (p < 0.001). However, it was difficult to differentiate between its neuroprotective and symptomatic effects.
In another study spanning 7 years, early PD patients who received selegiline had lower clinical deterioration and levodopa requirements compared to placebo.[32] This was a considerably unexpected finding, since selegiline is only mildly effective as monotherapy.
Rasagiline
Rasagiline is a more potent MAO-B inhibitor than selegiline. It has antioxidant properties, and increased survival of dopamine-containing neurons in preclinical studies.[45]
| Rasagiline in Early Monotherapy for Parkinson’s Disease Outpatients (TEMPO)Study | | |
In this trial, 404 early PD patients not requiring dopaminergic therapy were randomized to receive 1 or 2 mg of rasagiline per day for 12 months or placebo for 6 months, followed by 2 mg of rasagiline.[34] At 12 months, the UPDRS score revealed that patients in the placebo group had greater clinical deterioration than rasagiline group, suggesting that rasagiline-induced benefit exceeded a simple beneficial effect. This was true even at 6.5 years of follow-up, despite addition of other antiparkinsonian medications.
| Attenuation of Disease Progression with Azilect Given Once-Daily (ADAGIO) Study | | |
In this double-blind study, early- and delayed-start rasagiline in 1- and 2-mg doses were compared for their neuroprotective effects.[35] A total of 1091 untreated PD patients were enrolled. Of these, 273 were in the early-start 1 mg/day arm, 270 in the delayed-start 1 mg/day arm, 273 in the early-start 2 mg/day arm, and 275 in the delayed-start 2 mg/day arm. In the early-start group, the drug was given for 72 weeks. In the delayed-start arm, 36 weeks of placebo was followed by 36 weeks of the drug. A significant improvement in UPDRS scores were observed with 1 mg but not 2 mg of rasagiline in this 18-month trial.
Multiple reasons have been postulated for failure of the 2-mg dose to show a neuroprotective benefit. Symptomatic benefit may have masked its disease-modifying effect; however, symptomatic benefit was equal between both doses in the first phase, and MAO-B is almost completely inhibited with both doses. Another reason proposed is that its disease-modifying effect may be independent of MAO-B inhibition and more potent at lower doses. However, the propargylamine compound TCH346 failed to show any benefit in a large-scale trial.
Safinamide
Safinamide exerts a dual action in dopaminergic and extradopaminergic pathways. In addition to its MAO-B inhibitory effect, it modulates glutamate release through effects on sodium and calcium channels. Preclinical studies in animal PD models demonstrate its anti-inflammatory and neuroprotective properties.[46] However, human trials are lacking.
Thus, there is no unequivocal evidence of neuroprotective effects of MAO-B inhibitors so far.
| Dopamine Receptor Agonists (DRA) | | |
DRAs potentially protect nigrostriatal dopaminergic neurons from oxidative damage and spare levodopa. In addition, DRAs lead to a reduction in dopamine release by autostimulation of dopamine receptors. In multiple animal studies, DRAs were demonstrated to avert nigrostriatal dopaminergic cellular loss. Multiple clinical studies have addressed this effect.
Comparison of the Agonist Pramipexole with levodopa on motor complications of Parkinson’s disease (CALM-PD)
Pramipexole was compared to levodopa with positive results.[47] 301 patients were randomized to receive active pramipexole+ placebo levodopa or active levodopa + placebo pramipexole. Significantly lesser patients (28%) in pramipexole arm developed wearing off, dyskinesias, or on-off motor fluctuations versus levodopa arm (51%) (p < 0.001).
Pramipexole on Underlying Disease (PROUD)
Results of the CALM-PD study could not be affirmed in the early- versus delayed-start pramipexole groups in the PROUD study.[36] Here, patients were assigned to early- or delayed-start pramipexole (after 6–9 months of placebo). Mean change in UPDRS scores did not show significant difference between groups.
REAL-PET study
This study compared ropinirole to levodopa in 186 participants, in terms of fluorodopa uptake in substantia nigra over 24 months. It showed slower progression of PD with ropinirole than with levodopa.[37]
| Iron Chelators | | |
Clinical studies
Deferiprone
FAIR-PARK trial[48]: In this trial, deferiprone was administered at 30 mg/kg/day in the early-start group and after 6 months of placebo in the delayed-start group. Both groups showed significant attenuation of iron levels in the substantia nigra on MRI. Since the trial demonstrated feasibility, safety, and efficacy, a phase II trial of deferiprone, FAIR-PARK-II, is currently underway.[49]
Deferiprone PD[50]: In this pilot study, deferiprone in 20- and 30-mg/kg/day doses was compared with placebo for 6 months. No serious adverse effects were noted.
Thus far, evidence on iron chelation in PD progression remains inconclusive. Results from the large-scale (338 participants) FAIR-PARK-II trial are awaited.
| Calcium Channel Blockers | | |
Isradipine, a dihydropyridine channel blocker that penetrates the cerebrospinal fluid (CSF) has been evaluated as a neuroprotective agent in animal PD models.[51]
| Safety, Tolerability, and Efficacy Assessment of Dynacirc CR in Parkinson’s Disease (STEADY-PD) Study | | |
In the phase II trial, early PD patients who did not require dopaminergic therapy were randomised in a 1:1:1:1 ratio to receive 5, 10, 20 mg of isradipine or placebo.[38] Maximum tolerable dose was 10 mg. However, in the phase III trial published in 2020, there was no significant change in the Movement Disorders Society-UPDRS (MDS-UPDRS) total scores after 36 months of isradipine treatment, indicating that it did not slow progression in early PD.[39]
| Others | | |
N-metyhl-D Aspartate Antagonists, Glucagon-like peptide -1 Receptor agonists, coenzyme Q, Creatinie, kynurine, urates, neurotrophic factors and miscellaneous drugs in combination have been assessed for neuroprotection in PD.[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75] Details of trials of these are attached as online supplement 1.
Caffeine
Caffeine exerts multiple beneficial effects in PD by acting on brain adenosine A2A receptors (antagonistic action). It exerts neuroprotective properties via effects on mitochondria, neuroinflammation, and excitotoxicity, and effects on gut microbiota and α-synuclein degradation. Evidence from six large-scale epidemiological studies has established a correlation between increased caffeine intake and decreased risk of PD. Initial evidence for its beneficial effects stemmed from results of the Honolulu Heart Program. In this program, 8004 Japanese-American men were followed up for >30 years. Daily caffeine consumption of at least 784 mg/kg reduced the risk of development of PD in those >65 years by five times compared to noncoffee drinkers, after adjusting for age and smoking.[76] A meta-analysis offered a nonlinear relationship between coffee intake and PD risk, with three cups per day offering maximum protection.[77] In animal studies, caffeine was shown to impart protection against degeneration of dopaminergic neurons.[78],[79] Based on the evidence available, pragmatic randomized controlled trials with long-term follow-up, assessing the role of caffeine in patients with prodromal PD may be undertaken.
Nicotine
The incidence of PD has an inverse relationship with nicotine intake in different forms such as cigarette smoking, tobacco, and dietary sources such as pepper.[80],[81],[82] The impairment of dopamine release is enhanced by the loss of nicotinic acetylcholine receptor activation, creating a potential role for nicotinic agonists.[83] In brain cell culture, nicotine was protective for dopaminergic cells.[84] However, research on its impact on disease progression needs further exploration.
| Tyrosine Kinase Inhibitors | | |
Proteolytic cleavage of protein kinase C is regulated by Abelson tyrosine kinase, which leads to activation of the mitochondrial apoptotic pathway, mitochondrial injury, and cell death. Nilotinib has good CNS penetration and bioavailability. Several preclinical studies on animal PD models have suggested potential neuroprotection using tyrosine kinase inhibitors. In a randomized clinical trial using nilotinib in PD, 76 patients with moderate PD were randomized in a 1:1:1 ratio to receive placebo, 150 mg, and 300 mg of nilotinib once daily for 6 months.[43] Although the primary outcome of safety and tolerability was achieved, efficacy and response in terms of CSF nilotinib level and biomarkers showed a negative trend.
Immunotherapy
Cell-to-cell propagation of pathological α-synuclein confirmations via exosome release and endocytic uptake enables seeding and recruitment of normal α-synuclein into pathological confirmation. Therefore, development of monoclonal antibodies targeting α-synuclein is an exciting therapeutic target. Active and passive immunization are being currently explored. [85,86] We have summarized immunotherapy trials in [Table 2]. | Table 1: Major clinical trials for neuroprotection in Parkinson’s disease patients
Click here to view |
| Non-pharmacological Methods of Neuroprotection | | |
Different neuroprotective surgical strategies and exercise/lifestyle methods have been assessed for neuroprotection in PD.[44],[87],[88],[89],[90] Details are in online supplement 2.
| New Agents with Pathophysiology-Based Targets | | |
Several agents are currently under development as potential neuroprotective agents against PD. Sargramostim (T-cell modulator) and Inzomelid, which is an NLRP3 inflammasome inhibitor, have both completed phase I trials. Simvastatin, an HMG-CoA inhibitor, has shown some efficacy in the MPTP mouse model in an ongoing phase II trial (NCT02787590. In addition, azathioprine, an inhibitor of nucleic acid synthesis, is undergoing a phase II study (EudraCT 2018-003089-14). [Table 3] lists further details about these proposed agents. | Table 3: Evaluation of new agents for their role in neuroprotection in PD
Click here to view |
| Reasons for Lack of Success of Neuroprotective Strategies | | |
From the above discussion, it is apparent that despite benefits in preclinical trials, similar results were not observed in clinical settings. Multiple factors are responsible for this.
Markers or metrics of neuroprotection are often inadequate in measuring its true extent. To date, most studies have employed clinical scales, functional imaging and neuropathology. These markers only target the nigrostriatal dopaminergic systems, whereas PD affects multiple neurotransmitter pathways. The usual clinical scale employed is the UPDRS scale, which relies on motor deficits. Confounding symptomatic effects on motor function with different agents or even other therapies affect assessment of their neuroprotective effects. Among errors in research methodology, one factor that separates preclinical and clinical studies is use of chemically induced in vitro and animal PD models, which do not truly represent actual PD pathology in humans. Another noteworthy flaw in previous research methods is that PD is not a single disease but a combination of multiple biological entities that share clinical features. Therefore, a “one-size-fits-all” approach may not suffice.[13] Moreover, study populations in most previous clinical studies included patients who already had significant clinical manifestations suggesting significant dopaminergic loss, leaving little scope for neuroprotective agents to act on.
| Neuroprotective Trials in PD: The Way Forward | | |
In addition to the discovery of new agents, changes in current research methodologies are required. The first step would be designing better clinical, biochemical, imaging, or genetic biomarkers for early identification and recruitment of PD patients. The second strategy would be to conduct pragmatic randomized controlled trials enrolling selected patient subgroups with specific well-defined pathogenic/genetic abnormalities. Another strategy could be to evaluate synergistic combination therapies. In addition, neuroprotection studies should assess impact on nonmotor outcomes (rather than only motor outcomes), which remarkably affect quality of life. Finally, neuroprotective strategies should assess not only drug therapies, but also lifestyle modification.
| Conclusions | | |
To date, no neuroprotective agent has shown demonstrable efficacy in PD. Due to the heterogeneous nature of PD, it is unlikely that any single agent will completely cease neurodegeneration. Furthermore, with enhanced recognition of phenotypic, genetic, and molecular subtypes in PD, neuroprotection should traverse the path of precision medicine, pragmatic trials, combination therapies, lifestyle interventions, and refined outcome assessment strategies, if we are to see some light at the end of the tunnel.
Author Contribution
1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript preparation: A. Writing of the first draft, B. Review and Critique.
D. G.: 1ABC, 2B, 3AB; S. D.: 1ABC, 2ABC, 3B
Ethical compliance statement
The authors confirm that neither informed patient consent nor the approval of an institutional review board was necessary for this work. The authors confirm that they have read the journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Dr. Soaham Desai will act as the guarantor and corresponding author of this article.
Financial support and sponsorship
None.
Conflicts of interest
The authors have no conflicts of interest to declare.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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