GRAPHICAL ABSTRACT

Parkinson’s disease (PD) is characterized by progressive dopaminergic and nondopaminergic neuronal degeneration, which contributes to motor and nonmotor symptoms, and affects millions of individuals worldwide [1]. Despite significant advancements in symptomatic treatments, these interventions fail to modify the course of neurodegeneration, highlighting the urgent need for disease-modifying therapies (DMTs) that can slow or arrest disease progression [2].

Lewy bodies, resulting from α-synuclein aggregation, are the core pathological feature of PD [1]. Neuroinflammation, proteasome and lysosome dysfunction, and mitochondrial dysfunction and α-synuclein propagation (i.e., cell-to-cell transmission of α-synuclein) are significant factors in the pathophysiology of PD (Figure 1) [3,4]. A recent review of the clinical registry identified only 38 ongoing phase II or phase III pharmacological or biological treatments for disease modification in PD [5]. Moreover, the number of randomized clinical trials of DMTs for PD has not increased since 2020. Despite the substantial potential value of effective DMTs for PD, this area of research is considered high risk by the pharmaceutical industry, particularly because of the low clinical trial success rate. Notably, the challenges that contribute to repeated failures in phase III trials are complex and multifactorial. Disease heterogeneity, lack of reliable biomarkers for early diagnosis and disease progression, and limitations in trial design may limit the success of DMTs in the PD field [6,7]. Additionally, the neurodegenerative processes underlying PD are multifaceted and involve not only dopaminergic neuron loss but also multiple pathomechanisms. This complicates the identification of single agents capable of modifying disease progression [3,8].

DRUG REPOSITIONING AND REPURPOSING

Drug repositioning in the biopharmaceutical industry refers to the process of developing a drug for a new indication that differs from its original purpose, with the new indication taking precedence during the development phase prior to approval. In contrast, drug repurposing involves applying existing drug compounds to address new therapeutic conditions; specifically, it is a pathway accessible to academic institutions, government and research councils, charities, and nonprofit organizations, complementing the efforts of pharmaceutical and biotech companies [9]. Both repositioning and repurposing provide promising strategies to enhance traditional drug development and expedite the introduction of new treatments for PD in clinical practice. When conducting phase II trials for repurposed drugs, it is crucial to identify the optimal target population for the therapy and align it with the mechanism of action of the treatment. A notable example of this in PD is amantadine, which provides symptomatic relief of motor symptoms or exerts an antidyskinetic effect [10].

A significant advantage of this approach is that the safety profile of the candidate compound has already been established, eliminating the need for further preclinical safety testing, chemical optimization, or toxicology studies. Notably, this substantially reduces both the time and cost required to advance potential treatments in clinical trials. Furthermore, drugs already on the market typically have extensive safety data from prior regulatory programs, postmarketing surveillance, and safety monitoring. This well-documented safety profile often provides a strong foundation, or “freedom to operate,” particularly when existing drugs are repurposed for vulnerable populations, such as individuals with PD. Additionally, drug repurposing may bypass early developmental stages, including preclinical testing and phase II and phase IIa trials, which are time intensive and associated with high rates of drug attrition. Many hidden costs in drug development, such as formulation optimization, manufacturing processes, and drug-drug interaction studies, are also often addressed by the original developer. Although the average cost of bringing a drug to market is estimated at $5.6 billion, programs focused on repurposed drugs can significantly lower these expenses [11]. Furthermore, for repurposed agents, clinical evidence of efficacy may already exist through pathophysiological insights, epidemiological studies, open-label trials, or preliminary clinical data, providing a valuable supplement to the evidence base, particularly given the limitations of animal models.

Various strategies can be used to identify potential drug candidates for repurposing. One approach involves analyzing large datasets to uncover drug-related patient outcomes that might otherwise go unnoticed [12,13]. Another method, namely, hypothesis-driven repurposing, integrates knowledge of the disease and the properties or targets of existing drugs to pinpoint promising candidates [14]. Moreover, high-throughput screening using in vitro models to evaluate the effects of compounds on mechanisms such as α-synuclein aggregation is another useful technique [15]. A newer approach leverages disease-associated transcriptional signatures to identify potential therapies [16]. Combining these methods with a manual review of the literature is yet another strategy for identifying repurposing candidates. However, the available evidence varies among compounds; some may have robust in vitro or in vivo data, whereas others may rely on strong epidemiological findings. Notably, any proposed treatment, such as that for older adults with PD, should be appropriate for the target population. Addressing this complexity can be achieved by systematically reviewing the evidence and incorporating expert consensus methodologies such as the International Linked Clinical Trials Initiative (iLCT) [17]. This standardized method combines evidence review with iterative expert re-evaluation to establish priorities and select viable candidates.

We aim to discuss the drugs among the prioritized candidate drugs designated by the iLCT committee that have undergone or are currently undergoing clinical trials, as well as memantine, which has been investigated in our own research. Clinical trials of repurposed drugs for PD are presented in Table 1. Additionally, Figure 2 illustrates the mechanisms by which each drug discussed in this review is expected to exert a promising disease-modifying effect on α-synuclein, the central pathological hallmark of PD. The drug repositioning evidence levels for each drug [18], ranging from 0 (prediction only) to 4 (well-documented clinical endpoints), are illustrated in Figure 3.

PRIORITIZED DRUGS IN PREVIOUS RESEARCH

Glucagon-like peptide-1 receptor agonists

Owing to their potential neuroprotective properties in PD, glucagon-like peptide-1 (GLP-1) receptor agonists represent a category of antidiabetic medications that have garnered interest. The main actions of GLP-1 are to control glucose levels by stimulating insulin secretion and inhibiting glucagon secretion. However, GLP-1 is degraded by dipeptidyl peptidase-4 (DPP-4), leading to the formation of inactive metabolites. Consequently, GLP-1 receptor agonists, such as exenatide, lixisenatide, and liraglutide, which are resistant to DPP-4 degradation, are frequently utilized in the management of type 2 diabetes mellitus [19,20]. Both GLP-1 and its receptor are expressed in neuronal tissues, and their activation has been associated with beneficial outcomes in terms of cell proliferation, neurogenesis, and apoptosis [21]. Additionally, insulin resistance has attracted attention as a potential contributor to neurodegenerative processes [22]. Specifically, research indicates that GLP-1 receptor agonists may be associated with a reduced risk of developing PD among individuals with diabetes [13], and these agents have demonstrated neuroprotective effects in various models of neurotoxicity and α-synucleinopathy related to PD [23-25]. A proof-of-concept, single-blind study involving 21 patients with moderate PD who received exenatide for 12 months revealed sustained improvements in motor and cognitive functions for up to 14 months posttreatment, even after a 2-month wash-out period [26]. Furthermore, a phase IIb clinical trial successfully met its primary endpoint, showing a significant reduction in the progression of motor symptoms, as assessed by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, following 48 weeks of double-blind treatment [27]. Similarly, the potential of another GLP-1 receptor agonist, lixisenatide, in the treatment of PD has attracted considerable attention due to promising findings [28]. Compared with those receiving placebo, participants receiving lixisenatide exhibited decreased disability, as measured by the MDS-UPDRS part III, with these improvements observed in both the on- and off-medication states. This finding suggests that lixisenatide has disease-modifying effects that extend beyond enhancing the efficacy of existing therapeutic interventions.

In contrast, NLY-01, which is a longer-lasting version of exenatide, failed to show effectiveness on disease progression in patients with PD after 36 weeks of treatment [29]. Unlike other studies, the NLY-01 study was conducted in patients with drug-naïve PD, and its negative results suggest that the effects of GLP-1 receptor agonists observed in other clinical trials may be more likely to represent a symptomatic effect by enhancing the efficacy of levodopa rather than a true disease-modifying effect. Similarly, although some nonmotor symptoms improved, administration of liraglutide did not result in a difference in the MDS-UPDRS part III score between the treatment and control groups [30].

Nevertheless, GLP-1 receptor agonists are anticipated to have potential disease-modifying effects on PD. However, a recent phase III clinical trial of exenatide (exenatide-PD3) indicated a lack of efficacy. Although the final results have not yet been published, they are expected to provide valuable insights for future clinical trials of other drugs, including lixisenatide.

DPP-4 inhibitors

Preclinical research has indicated that DPP-4 inhibitors may protect dopaminergic neurons from degeneration, promote neuroplasticity, and reduce neuroinflammation [31-35]. Although their primary mechanism involves enhancing GLP-1 signaling and its associated anti-inflammatory effects [36], direct inhibition of DPP-4 may provide additional anti-inflammatory benefits [37]. This dual mechanism suggests that DPP-4 inhibitors can have comprehensive neuroprotective effects in patients with PD. In addition, given that DPP-4 inhibitors are small molecules, they offer practical advantages over larger peptide-based therapies such as GLP-1 receptor agonists, making them more suitable for patients with PD [38].

A nationwide case-control study conducted in Sweden indicated that the administration of DPP-4 inhibitors is linked to a reduced risk of developing PD in the future [39]. Similarly, another cohort study revealed that the utilization of DPP-4 inhibitors and/or GLP-1 receptor agonists was associated with a lower incidence of PD than other oral antidiabetic medications [13]. Furthermore, research by Lin et al. [40] revealed that diabetic patients receiving DPP-4 inhibitors, particularly vildagliptin, presented a significantly lower risk of PD than did those treated with alternative oral antidiabetic drugs. Additionally, a recent investigation highlighted that diabetic patients with PD treated with DPP-4 inhibitors demonstrated greater baseline dopamine transporter availability and a slower escalation in levodopa-equivalent dosage over time, indicating potential beneficial effects on motor outcomes within this population [41].

A multiarm phase II trial conducted in Australia recruited 240 participants who were randomly assigned to one of four arms: a placebo arm against an albuterol arm, a nilvadipine arm, and an alogliptin arm, which is a DPP-4 inhibitor (registration number: ACTRN12620000560998). Additionally, a small phase IV study investigated the beneficial effects of sitagliptin, a DPP-4 inhibitor, and dapagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, on Lewy body disease (ID: NCT06263673). Although the recent phase III trial of exenatide yielded negative results, raising doubts about the effectiveness of DPP-4 inhibitors for treating PD, DPP-4 has various nonglycemic effects beyond its mechanism of inhibiting GLP-1 degradation [42]. Notably, DPP-4 inhibitors play a critical role in modulating inflammatory responses, which suggests potential therapeutic effects in PD [37]. For example, DPP-4 influences signaling pathways related to inflammatory cytokines, indicating the possibility of suppressing microglial activation and neuroinflammation in the brain. Additionally, DPP-4 inhibitors may affect cellular processes such as apoptosis, which could play a significant role in neurodegenerative diseases such as PD [43]. Therefore, drawing definitive conclusions about the potential disease-modifying effects of DPP-4 inhibitors in PD remains challenging. Further studies are needed to evaluate these effects, particularly through experimental approaches that focus on nonglycemic effects. Such research could provide more specific and in-depth insights into this area.

Ambroxol

In 2009, ambroxol hydrochloride, a commonly used expectorant for the management of respiratory conditions characterized by excessive mucus production, was identified as a chaperone for the lysosomal enzyme β-glucocerebrosidase (GCase), which is encoded by the GBA1 gene, during a screening of drugs approved by the Food and Drug Administration [44]. This finding indicates the potential for repurposing ambroxol for the treatment of PD, given that genetic mutations in the GBA1 gene are the strongest genetic risk factor for PD [45]. Under normal circumstances, GCase operates as a lysosomal enzyme; however, mutations in GBA1 result in the enzyme being sequestered within the endoplasmic reticulum (ER), leading to its degradation by the proteasome [46]. This mechanism is believed to contribute to the lysosomal dysfunction observed in both Gaucher disease and PD. Patients with PD with GBA1 mutations exhibit symptoms similar to those of patients with idiopathic PD, albeit with a more aggressive clinical course characterized by a younger onset of symptoms, rapid motor progression, and rapid cognitive decline [47]. Furthermore, subsequent to the identification of ambroxol’s function as a GCase chaperone, research has demonstrated its capacity to increase GCase levels within the central nervous system in various in vitro and in vivo models [48-50]. Ambroxol translocates mutant GCase from the ER to lysosomes, thereby increasing cellular GCase activity [51]. Additionally, ambroxol has been shown to decrease the levels of α-synuclein and its phosphorylated variant in the brains of mice that overexpress human α-synuclein [49].

Motivated by these preclinical findings, the phase IIa “AiM-PD” trial started and enrolled 18 patients with PD who were administered escalating doses of ambroxol (up to 1,260 mg/day) over 6 months. Recent results indicated that ambroxol was tolerable for patients with PD and that adverse events were not significant. Additionally, ambroxol significantly increased GCase levels in the cerebrospinal fluid (CSF) by approximately 35% [52]. However, due to the open-label design and limited duration of the study, these results require cautious interpretation. Two clinical trials are currently underway to expand these findings. Specifically, the AMBITIOUS trial, a phase II study, examined the impact of ambroxol on cognitive decline in PD patients with GBA1 mutations. This double-blind, placebo-controlled trial evaluated primary cognitive outcomes and secondary measures, including motor and nonmotor symptoms and biomarkers of neurodegeneration. Additionally, the ASPro-PD trial, a phase III study, aimed to assess the safety, tolerability, and potential disease-modifying effects of ambroxol in a broader population of patients with PD. These trials represent essential advancements in efforts to translate preclinical success into clinically significant outcomes. Additionally, another phase II study investigated ambroxol in 70 PD patients with dementia [53]. In Norway, the ANeED study is recruiting participants, focusing on dementia with Lewy bodies (DLB) in a phase IIa multicenter trial [54]. These ongoing clinical trials reflect growing optimism about the therapeutic potential of ambroxol for PD, as researchers aim to translate promising preclinical findings into meaningful clinical outcomes for patients.

Calcium channel blockers

Neurodegeneration in PD is influenced by a complex interplay of genetic and environmental factors, along with the selective vulnerability of specific neuronal populations, particularly dopaminergic neurons, in the substantia nigra (SN). However, the specific cell-autonomous mechanisms underlying this vulnerability remain unclear. Notably, neurons that depend on Ca(v)1.3 L-type calcium channels for maintaining autonomous pacemaking activity may be especially vulnerable to mitochondrial oxidative stress, suggesting that the inhibition of L-type calcium channels could confer neuroprotective benefits [8]. Furthermore, recent investigations have demonstrated that L-type, N-type, and T-type calcium channel blockers (CCBs) can inhibit the transmission of α-synuclein [55]. Isradipine, a dihydropyridine CCB with a strong affinity for L-type calcium channels that is approved for hypertension treatment, has exhibited neuroprotective effects in animal models of PD [56,57]. Additionally, epidemiological studies have suggested that various CCBs are associated with a significantly lower risk of future PD diagnosis [12,58].

In light of these findings, a phase II randomized clinical trial was conducted to assess the tolerability of isradipine [59]. This trial established 10 mg daily as the maximum tolerable daily dose because higher doses are associated with adverse effects. Using this dosage, the STEADY-PD III trial, a large phase III multicenter, randomized, double-blind, placebo-controlled study, was initiated to evaluate the efficacy of isradipine in decelerating the progression of PD [60]. The trial enrolled 336 patients with drug-naïve early-stage PD and randomized them to receive either isradipine or a placebo for 36 months. The primary endpoint was the change in the Unified Parkinson’s Disease Rating Scale (UPDRS) parts I to III score, measured in the on-medication state, from baseline to 36 months. The results showed that isradipine did not yield any significant benefits in terms of slowing clinical progression, and no significant differences were observed in either the primary or secondary outcome measures. The failure of the STEADY-PD III trial can be attributed to several key factors. First, the primary outcome measure (UPDRS score in the on-medication state) may not have been sensitive enough to detect disease-modifying effects, as symptomatic treatment could have masked subtle differences. Second, insufficient target engagement in the brain raises concerns about whether the administered dose effectively blocks L-type calcium channels, although higher doses are likely limited by side effects such as orthostatic hypotension. Finally, slow disease progression in the placebo group may have reduced the ability of the trial to detect meaningful differences, suggesting that longer follow-up or biomarker-based assessments might be necessary for future studies. However, a recent study indicated that the use of CCBs has a protective effect against conversion to dementia [61], suggesting the need for further investigation of the potential beneficial effects of CCBs on the nonmotor symptoms of PD. Additionally, the secondary analysis of the phase II clinical trial suggested potential benefits [62]. These findings highlight the complexities of translating neuroprotective strategies from preclinical models to clinical practice and underscore the need for further research to better understand the role of CCBs in PD, particularly their potential effects on nonmotor symptoms and disease-modifying outcomes. Regrettably, no further research is currently being conducted on isradipine or other CCBs for PD.

Statins

Statins are widely prescribed not only for the primary and secondary prevention of cardiovascular diseases through the inhibition of cholesterol biosynthesis but also as potential neuroprotective agents in the context of neurological disorders owing to their various pleiotropic effects [63]. The impact of statin treatment on the pathogenesis of PD in experimental models, as well as its epidemiological association with PD incidence, remains highly contentious. Specifically, whereas preclinical investigations have indicated that statins may confer protective benefits against the aggregation of α-synuclein and the degeneration of dopaminergic neurons in PD [64-66], some studies have reported adverse effects of atorvastatin and simvastatin on the survival of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD [67]. Furthermore, epidemiological research has suggested that statins may be associated with a reduced incidence of PD [68,69]; however, observational studies conducted by Huang et al. [70,71] have posited that statins could negatively influence PD incidence by lowering cholesterol levels. Additionally, a recent investigation indicated that the use of statins may adversely affect baseline nigrostriatal dopamine degeneration and long-term motor and cognitive outcomes in individuals with PD [72].

To date, only two clinical studies have examined the effects of statins on PD. A phase II trial using simvastatin, known as PD-STAT, enrolled 230 participants with moderate PD and assessed the daily administration of either 40 mg simvastatin or a placebo over two years. This study not only failed to demonstrate that simvastatin is effective in slowing the progression of PD but also showed worsening motor symptoms in the simvastatin-treated group [73], leading to the discontinuation of further clinical research. Another nationwide phase II study in Taiwan using lovastatin enrolled 77 patients with early-stage PD, and lovastatin 80 mg or placebo was administered for 48 weeks with a 4-week wash-out period [74]. The MDS-UPDRS part III scores at 52 weeks were not significantly different between the two groups. Although it did not meet the primary outcome in the phase II clinical trial, it demonstrated a possible beneficial effect in terms of dopaminergic cell loss as assessed by 18F-fluorodopa positron emission tomography, suggesting the potential for further research. These findings highlight the complex and conflicting nature of the effects of statins on PD, underscoring the need for further well-designed clinical studies to clarify their potential therapeutic roles and underlying mechanisms in PD.

Iron-chelating agents

Postmortem studies have demonstrated enormous iron accumulation in patients with PD [75]. Iron is associated with oxidative stress and ferroptosis (i.e., an iron-dependent form of cell death) [76]; moreover, it is believed to affect the proteasome, which subsequently modulates the clearance of aggregated α-synuclein [77]. Notably, deferiprone, an iron-chelating agent, can cross the blood-brain barrier. Specifically, previous in vitro and in vivo studies have shown that deferiprone treatment reduces oxidative stress, improves motor symptoms, and increases striatal dopamine levels [78]. A preliminary study indicated that early intervention with deferiprone led to a reduction in nigral iron accumulation and an improvement in motor function in patients with early-stage PD [78]. Additionally, a randomized, double-blind, placebo-controlled trial demonstrated that a 6-month course of deferiprone was well tolerated and effectively decreased iron levels in specific regions of the brain [79].

These findings encourage further exploration of iron chelators as potential therapeutic agents for PD. Recently, a multicenter, phase II, double-blind, randomized trial (FAIRPARK-II) investigated deferiprone in patients with newly diagnosed PD [80]. This trial enrolled 372 participants who had not received levodopa treatment and randomly assigned them to receive either deferiprone (15 mg/kg twice daily) or placebo for 36 weeks. Although magnetic resonance imaging scans confirmed reduced brain iron deposition in the deferiprone-treated group, the MDS-UPDRS part 3 scores unexpectedly worsened in this group compared with those in the placebo group. This divergence began at 3 months and persisted throughout the 9 months. Furthermore, no difference in dopamine transporter density was observed between the groups, suggesting that iron chelation therapy does not have disease-modifying effects. Recent investigations have also evaluated the efficacy of deferiprone in patients with newly diagnosed and early-stage PD using the SKY and EMBARK studies. The SKY study, which included patients with early-stage PD receiving stable dopaminergic therapy, revealed no significant benefit of deferiprone in improving motor symptoms, except for a nonsignificant trend toward improvement at a dose of 600 mg twice daily. Conversely, the EMBARK study, which examined treatment-naive and dopaminergic-treated patients, revealed a significant worsening of motor symptoms in the treatment-naive group; however, the dopaminergic-treated group exhibited no significant motor improvements. Both studies concluded that deferiprone does not provide substantial motor function benefits in patients with PD and highlighted the potential risks when it is used without concurrent dopaminergic therapy [81].

Abelson murine leukemia viral homolog 1 inhibitors

Abelson murine leukemia viral homolog 1 (c-Abl) tyrosine kinase performs various biological functions, including regulating synapse formation, neurite outgrowth, and neurogenesis in the central nervous system [82]. Interestingly, c-Abl activation increases with age and is elevated in specific brain regions of patients with PD, as well as in PD animal models. This aberrant activation has been linked to the phosphorylation of α-synuclein at tyrosine 39 and serine 125, leading to α-synuclein aggregation [83]. Nilotinib, which is an inhibitor of c-Abl tyrosine kinase, has shown promise in preclinical PD models. In the MPTP mouse model of PD, nilotinib reduced c-Abl activation, preserved dopamine neurons, and mitigated behavioral deficits [84]. Notably, a preliminary study involving 12 patients with advanced PD demonstrated mild improvements in motor and cognitive functions after 24 weeks of treatment, which were reversed by 36 weeks [85]. Although these findings generated enthusiasm, their interpretation was limited by the study’s small size, lack of a control group, and potential confounding effects, such as monoamine oxidase-B inhibitor withdrawal, influencing biomarker changes such as increased CSF homovanillic acid levels [86].

Since then, two randomized phase II clinical trials have investigated the safety and tolerability of nilotinib at daily doses of 150 mg and 300 mg compared with placebo [87]. A single-center study with 75 participants reported increased dopamine metabolite levels in the CSF in some nilotinib-treated groups but reported no significant differences in motor or nonmotor outcomes. However, this study was not designed to evaluate its efficacy. Although adverse events were comparable between the groups, serious adverse events, including four cardiovascular events, occurred more frequently in nilotinib-treated patients. A larger multicenter trial (NILO-PD) with a similar design produced conflicting findings [88], demonstrating the poor central nervous system penetration of nilotinib and no changes in dopamine metabolites.

These conflicting outcomes raise questions regarding the feasibility of pursuing further trials of nilotinib for PD. Additionally, although the final results have not yet been published, a recently conducted phase II trial using vodobatinib in early-stage PD reported that this novel c-Abl inhibitor did not show any evidence of treatment benefits in patients with PD.

Memantine

Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has garnered attention for its potential role in PD, particularly through the modulation of α-synuclein transmission. Experimental evidence highlights that NMDA receptors play crucial roles in facilitating the cell-to-cell propagation of α-synuclein aggregates [89]. In vitro and in vivo studies have demonstrated that memantine effectively inhibits this transmission, suggesting its potential as a disease-modifying agent in PD [90].

Clinically, memantine has been evaluated for its effects on cognitive and behavioral symptoms in PD dementia and DLB. A pivotal randomized controlled trial reported that memantine led to significant improvements in behavioral symptoms, including reduced agitation and aggression, in patients with DLB. However, their effects on global cognition are modest and variable. Furthermore, in patients with PD dementia, memantine tends to improve cognitive function, particularly in domains such as attention and executive function. However, the results did not reach statistical significance [91]. Despite these promising outcomes, subsequent meta-analyses have raised questions about the robustness of these findings, particularly in placebo-controlled trials, where the observed benefits for cognition were minimal compared with those of open-label studies [92]. Consequently, current guidelines do not recommend memantine for routine use in improving cognitive function in patients with PD. Nevertheless, experimental studies suggesting its ability to inhibit α-synuclein propagation provide a rationale for exploring memantine as a disease-DMT for PD [89,90]. This hypothesis is currently under investigation in an ongoing clinical trial (ID: NCT03858270) that aims to assess the impact of memantine on slowing disease progression through the modulation of α-synuclein dynamics.

RECENTLY UPDATED LIST OF PRIORITIZED CANDIDATE DRUGS

Fasudil

Fasudil, a Rho-associated protein kinase (ROCK) inhibitor, has garnered attention as a potential therapeutic agent for PD owing to its multifaceted neuroprotective mechanisms. Fasudil has a unique ability to modulate pathological α-synuclein aggregation through both direct and indirect pathways, making it a promising candidate for clinical exploration. In particular, fasudil directly binds to the C-terminal region of α-synuclein, specifically targeting tyrosine residues Y133 and Y136, as revealed by nuclear magnetic resonance spectroscopy. This interaction disrupts α-synuclein aggregation, delays amyloid fibril formation, and reduces the accumulation of toxic high-molecular-weight aggregates. In vitro studies in H4 human neuroglioma cells and cell-free aggregation assays revealed significant anti-aggregation effects at micromolar concentrations [93]. Notably, long-term administration of fasudil in transgenic mouse models of PD (e.g., α-SynA53T mice) not only attenuated α-synuclein aggregation but also improved motor and cognitive functions [94]. Behavioral assays, such as CatWalk gait analysis and novel object recognition tests, demonstrated significant recovery, elucidating the potential of fasudil to modify disease progression. Furthermore, immunohistochemical analysis revealed reduced α-synuclein levels in the SN. In addition to its direct effects on α-synuclein, fasudil inhibition by ROCK contributes to its neuroprotective profile. ROCK inhibition has been shown to enhance regenerative sprouting, mitigate dopaminergic neuronal death, and reduce neuroinflammation in toxin-induced PD models [95]. These complementary pathways strengthen the potential of fasudil as a multifaceted DMT.

Moreover, the dual ability of fasudil to directly target α-synuclein aggregation and modulate neuroinflammatory and regenerative pathways via ROCK inhibition provides a strong mechanistic basis for its clinical application in PD. The translational potential of fasudil, demonstrated by its efficacy in both in vitro and in vivo models, supports its use in ongoing clinical trials aimed at evaluating its safety, tolerability, and therapeutic efficacy in slowing PD progression [96].

β2-adrenergic receptor agonists

β2-adrenergic receptor (β2AR) agonists have emerged as promising candidates for repurposing in PD due to their role in modulating α-synuclein expression. Mechanistically, β2AR activation reduces SNCA transcription through epigenetic regulation, specifically by decreasing histone histone 3 lysine 27 acetylation at the SNCA promoter and enhancer regions. Notably, preclinical studies have demonstrated that β2AR agonists, such as salbutamol and clenbuterol, can lower SNCA expression, reduce alpha-synuclein protein aggregation, and protect dopaminergic neurons from neurotoxin-induced degeneration [97]. Moreover, epidemiological analyses have further supported this potential, with longitudinal data from the Norwegian Prescription Database showing a reduced PD risk among salbutamol users (rate ratio: 0.66) [97]. Additionally, a meta-analysis reported a pooled adjusted risk ratio of 0.87 for PD among β2AR agonist users, suggesting a modest but consistent protective effect [98].

As mentioned previously, the ACTRN12620000560998 trial in Australia investigated the neuroprotective effects of albuterol in individuals with early PD, focusing on the ability of β2AR agonists to reduce alpha-synuclein pathology and modulate disease progression. These efforts highlight the growing recognition of β2AR agonists as potential disease-modifying agents, offering a novel approach for targeting the underlying molecular pathology of PD.

Terazosin

Impaired energy metabolism and bioenergetic deficits are crucial for PD pathogenesis [99]. In this context, terazosin, an α1-adrenergic receptor antagonist with the unique ability to increase glycolysis by activating phosphoglycerate kinase 1 (PGK1), has emerged as a promising candidate for disease modification in PD [100].

Terazosin binds to PGK1, the first adenosine triphosphate (APT)-producing enzyme involved in glycolysis, thereby stimulating its activity and increasing ATP production. This mechanism has been demonstrated in preclinical models and patient-derived data, suggesting that terazosin addresses the bioenergetic deficits observed in PD [100]. Furthermore, in toxin-induced and genetic models of PD, including MPTP-treated mice and α-synuclein-overexpressing systems, terazosin increased brain ATP levels, prevented dopaminergic neuron loss, and mitigated motor dysfunction. In another study, terazosin prevented cognitive decline in animal models in which dopamine was depleted in the ventral tegmental area [101].

In terms of clinical evidence, data from large-scale pharmacoepidemiologic studies suggest that terazosin and related glycolysis-enhancing drugs (e.g., doxazosin and alfuzosin) are associated with slower progression of motor symptoms and a reduced hazard of developing cognitive impairments and PD-related dementia [100]. In addition, analyses of large health care databases, such as the Danish Nationwide Health Registries and MarketScan, demonstrated a reduced risk of developing PD in patients using a glycolysis-enhancing α1-blocker compared with tamsulosin, a similar α1-blocker without glycolysis-enhancing effects [102]. Importantly, the dose-response relationships observed in this study further support a protective association. Finally, a 12-week pilot study evaluating terazosin in patients with PD demonstrated significant increases in brain and blood ATP levels, suggesting successful target engagement [103]. Although the study was not powered to evaluate its clinical efficacy, these findings support the hypothesis that increased glycolysis may modify disease progression.

SGLT-2 inhibitors

Emerging evidence suggests that SGLT-2 inhibitors, a class of oral antidiabetic drugs, possess antioxidative and mitochondrial protective properties, potentially offering neuroprotective benefits [104]. For example, dapagliflozin, an SGLT-2 inhibitor, has demonstrated neuroprotective effects in a rotenone-induced PD animal model, improving motor function, decreasing α-synuclein expression, and increasing dopamine and tyrosine hydroxylase levels, suggesting its potential to increase dopaminergic activity [105]. Furthermore, empagliflozin, another SGLT-2 inhibitor, exhibited restorative effects in a rotenone-induced PD rat model, enhancing motor function, as assessed by open field tests, grip strength assessments, and footprint gait analysis, while preserving neuronal integrity. Empagliflozin was found to reduce astrogliosis and microgliosis, decrease immunostaining for glial fibrillary acidic protein and ionized calcium-binding adaptor protein 1, and modulate the GRP78/PERK/eIF2α/CHOP ER stress pathway [106]. Additionally, empagliflozin downregulated miR-211-5p, diminished oxidative stress, and reduced the activation of astrocytes and microglia, as well as neuroinflammation, while promoting autophagy. These encouraging preclinical results highlight the necessity for further investigation of these agents in clinical trials, with dapagliflozin currently being assessed in clinical studies (ID: NCT06263673).

CONCLUSION

Given the significant burden of this neurodegenerative disorder on patients and the health care system, DMTs for PD remain a priority. Drug repositioning and repurposing offer a pragmatic and efficient pathway to address the unmet need for therapies that can slow or arrest disease progression. Promising candidates, such as GLP-1 receptor agonists, DPP-4 inhibitors, and ambroxol, have demonstrated potential through their diverse mechanisms of action, targeting key pathological features of PD, including α-synuclein aggregation, neuroinflammation, lysosomal dysfunction, and oxidative stress. However, the challenges faced in drug repurposing trials for PD highlight the need for more strategic approaches to improve success rates. First, refining outcome measures is essential, as traditional clinical scales may not effectively capture disease-modifying effects. Integrating biomarkers such as imaging markers or fluid-based biomarkers can provide more objective assessments of disease progression. Second, validating target engagement before large-scale trials is critical to ensure that repurposed drugs effectively reach and modulate their intended targets in the brain. Molecular imaging and pharmacodynamic biomarkers can play crucial roles in confirming this early. Third, optimizing dosing strategies is also important, as many repurposed drugs may require careful dose adjustments to balance efficacy with tolerability. Longer and adaptive clinical trial designs should be considered, allowing for flexible adjustments based on emerging data and enabling trials to capture subtle disease progression over extended periods. Finally, advancing precision medicine approaches, such as patient stratification based on genetic, biomarker, or disease progression profiles, can help identify subgroups more likely to benefit from specific repurposed drugs. By integrating these strategies, future drug repurposing trials for PD can be designed more effectively, increasing the likelihood of identifying successful disease-DMTs.

Collaborative efforts among academia, industry, and regulatory agencies are essential for optimizing clinical trial designs, refining target populations, and integrating biomarker-driven approaches. By leveraging advances in molecular biology, data analytics, and personalized medicine, this field can address the multifaceted challenges of PD drug development. Although the setbacks in phase III trials highlight the difficulties inherent in this endeavor, they also provide critical insights for refining future strategies. With continued innovation and commitment, drug repurposing and repositioning hold significant promise for transforming the treatment landscape of PD, ultimately improving the outcomes and quality of life of millions of patients worldwide.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2023-00209580).

Acknowledgments

Medical Illustration & Design (MID), as a member of the Medical Research Support Services of Yonsei University College of Medicine, providing excellent support with medical illustration.

Author Contributions

Conceptualization: Seong Ho Jeong, Phil Hyu Lee. Data curation: Seong Ho Jeong. Funding acquisition: Seong Ho Jeong. Investigation: Seong Ho Jeong, Phil Hyu Lee. Project administration: Seong Ho Jeong, Phil Hyu Lee. Resources: Seong Ho Jeong, Phil Hyu Lee. Software: Seong Ho Jeong. Supervision: Phil Hyu Lee. Validation: Phil Hyu Lee. Visualization: Seong Ho Jeong. Writing—original draft: Seong Ho Jeong. Writing—review & editing: Phil Hyu Lee.

Figure 1.

Pathophysiological mechanisms of α-synuclein in Parkinson’s disease. This figure illustrates the interplay between environmental factors, mitochondrial dysfunction, and oxidative stress in promoting the pathological expression of α-synuclein, a key protein implicated in Parkinson’s disease.

Figure 2.

Proposed mechanisms of drug repurposing of α-synuclein in Parkinson’s disease. This figure illustrates various repurposed drugs and their mechanisms of action targeting the core protein α-synuclein in Parkinson’s disease. The surrounding layers represent drug categories and their respective mechanisms of action. α-syn, α-synuclein; β2AR, β2-adrenergic receptor; GLP-1, glucagon-like peptide-1; DPP-4, dipeptidyl peptidase-4; SGLT-2, sodium-glucose cotransporter-2.

Figure 3.

Drug repositioning evidence levels in Parkinson’s disease. The figure categorizes various drug classes based on their level of clinical evidence for repurposing in Parkinson’s disease. The evidence levels are defined as follows: level 0, no evidence; includes in silico predictions without experimental validation; level 1, in vitro studies with limited value for predicting in vivo or human outcomes; level 2, animal studies with hypothetical relevance to human disease; level 3, incomplete studies in humans at appropriate doses, such as proof-of-concept trials or observational studies with limited clinical data; and level 4, well-documented clinical endpoints observed for the repurposed drug at doses within established safety limits. The evidence levels are depicted in the bars, with categories including “Ineffective in phase III trials” (orange), “Ineffective in phase II trials” (light yellow), “Ongoing clinical trials” (dark green), and “No current clinical trials” (light green). GLP-1, glucagon-like peptide-1; DPP-4, dipeptidyl peptidase-4; c-Abl, Abelson murine leukemia viral homolog 1; β2AR, β2-adrenergic receptor; SGLT-2, sodium-glucose cotransporter-2.

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