2024 Volume 13 Issue 4
Creative Commons License

Modern Pharmacological Treatment of Parkinson's Disease : Reviving Known Drugs and New Perspectives


, , , , , , ,
  1. SSG in the department of Pharmacology, Jagiellonian University Medical College, Cracow, Poland.
  2. Department of Pharmacology, Jagiellonian University Medical College, Cracow, Poland.
Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as tremor and rigidity, along with non-motor symptoms like cognitive decline and depression. Current dopaminergic therapies offer symptomatic relief but fail to halt disease progression, underscoring the urgent need for novel, disease-modifying treatments. This review examines the potential of repurposed drugs from various therapeutic categories—including immunomodulatory, cardiometabolic, and anti-infective agents—as promising therapeutic strategies for PD. Immunomodulatory agents such as c-Abl inhibitors (imatinib, nilotinib) and sargramostim have shown potential in reducing α-synuclein aggregation and neuroinflammation, although clinical outcomes have been mixed. Cardiometabolic drugs, notably glucagon-like peptide-1 agonists like exenatide, have demonstrated improvements in motor and cognitive symptoms, with ongoing phase III trials evaluating their disease-modifying potential. Anti-infective agents, including doxycycline and rifampicin, exhibit neuroprotective effects through anti-inflammatory and anti-aggregating actions. While some concerns regarding efficacy and toxicity persist, these repurposed drugs offer valuable insights into novel treatment approaches for PD. Additionally, emerging strategies such as gene therapy, enzyme replacement, and advanced drug delivery systems are discussed for their potential to address underlying disease mechanisms. Despite the absence of definitive disease-modifying therapies to date, the advancements in drug repurposing and innovative therapeutic approaches provide hope for future breakthroughs. Further large-scale clinical trials are necessary to confirm the efficacy and safety of these treatments.


Keywords: Parkinson's disease, Neurodegeneration, Drug repurposing, Immunomodulatory therapies, Disease-modifying treatments

INTRODUCTION

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily resulting from the loss of dopaminergic neurons in the substantia nigra (SN). These neurons play a crucial role in motor control, coordination, and various cognitive functions by producing dopamine. The depletion of dopamine leads to the hallmark motor symptoms (MS) of PD, which include tremors, increased muscle tone (rigidity), bradykinesia (slowness of movement), and postural instability, contributing to difficulties in gait and balance. In addition, PD progression varies significantly between individuals, and while the onset is often gradual, the disease inevitably worsens over time. Despite ongoing research, there is no disease-modifying treatment available for PD. However, symptomatic therapies and various interventions can alleviate motor symptoms and enhance the quality of life (QoL) for patients [1, 2].

In addition to the well-known motor symptoms, PD is also associated with a broad spectrum of non-motor symptoms (NMS), which can be equally, if not more, debilitating for patients. These non-motor symptoms include dysarthria (speech difficulties), dysphagia (swallowing difficulties), depression, anxiety, sleep disturbances, and cognitive impairments such as memory loss and executive dysfunction. Other prevalent NMS include autonomic dysfunctions such as constipation and seborrheic skin disorders [3-6]. The severity and manifestation of these symptoms vary widely among patients, with not all experiencing the full spectrum of NMS. These deficits have a substantial impact on patient outcomes and make clinical management of Parkinson's disease more difficult.

PD affects approximately 1 million individuals in the United States alone, with an average age of onset around 60 years [7]. The annual incidence rate in the U.S. is estimated at about 60,000 new cases [8]. Moreover, the prevalence increases with age, affecting 1-2% of individuals over 60 years old, and rising to nearly 4% in individuals over 80 years old [9]. The disease is more prevalent in men than in women, with a male-to-female ratio of about 1.5 to 1 [10]. Additionally, PD is more common among white populations compared to other racial or ethnic groups [11]. Globally, the burden of Parkinson's disease is expected to rise as the population ages, making it a significant public health challenge [12, 13].

Given the current limitations in treating PD and the anticipated rise in its global prevalence, there is an urgent need to explore new therapeutic fields. Recent research has started to investigate the potential repurposing of drugs from other medical fields, such as cardiology and immunology, for PD treatment. This approach involves targeting new molecular pathways and mechanisms that may help alleviate symptoms or slow disease progression. In this review, we have synthesized the latest findings in this area, particularly focusing on repurposed medications such as immunosuppressants and cardiovascular drugs. Our objective is to enhance understanding of these emerging therapies and discuss their potential to open new frontiers in PD management, aiming to improve patient outcomes and quality of life.

Background and disease pathology

At the molecular level, PD is thought to be related to a combination of abnormal protein accumulation, inflammation, and the generation of reactive oxygen species (ROS), all of which contribute to the degeneration of neurons in the substantia nigra (Figure 1). A hallmark of PD is the formation of abnormal protein aggregates known as Lewy bodies (LBs) within the nerve cells of the SN, which are primarily composed of alpha-synuclein, a protein expressed throughout the brain [14]. These aberrant protein aggregates cause neurones' regular functions to be disrupted, which eventually results in their death. Beyond Parkinson's disease (PD), Lewy bodies are also a feature of other neurodegenerative illnesses, like multiple system atrophy (MSA) and dementia with Lewy bodies, where their existence is associated with both motor and cognitive symptoms [15].

The role of alpha-synuclein in the development of Lewy bodies has been extensively studied. Alpha-synuclein is a 140 kDa protein encoded by the SNCA gene, and it is suggested to regulate neurotransmitter release and maintain the presynaptic cytoskeleton, as well as facilitate vesicular transport within cells [16-18]. Although its exact function remains unclear, alpha-synuclein is believed to play a critical role in maintaining neuronal integrity and modulating ion channel activity [18]. Furthermore, studies suggest that alpha-synuclein is involved in the regulation of oxidative stress and apoptosis [19, 20]. Research indicates that alpha-synuclein may promote apoptosis through interactions with mitochondria, which are essential for both energy production and the regulation of cell death [21, 22]. Genetic factors, including mutations in the SNCA gene and other related genes, have been implicated in the formation of Lewy bodies and the development of familial PD, though this form of the disease is rare [23, 24]. These genetic mutations are thought to increase susceptibility to PD and other alpha-synucleinopathies, highlighting the potential influence of heritable factors in what has traditionally been considered a sporadic or idiopathic disease [24].

 

Figure 1. The pathophysiology model of Parkinson’s disease. Abbreviations: SNCA, Synuclein Alpha Gene; PARK2, Parkin Gene; GBA, Glucocerebrosidase Gene; LRRK2, Leucine-Rich Repeat Kinase 2 Gene; PINK1, PTEN-induced kinase 1; α-Syn, Alpha-Synuclein; ROS, Reactive Oxygen Species; Fe²⁺, Iron ions (Ferrous); IL-1β, Interleukin-1 Beta; IL-6, Interleukin-6; TNFα, Tumor Necrosis Factor Alpha; VIR, Viruses; TOX, Toxins; and DAMPS, Damage-Associated Molecular Patterns.

Lewy bodies are not exclusive to the substantia nigra; they can also be found in other regions of the brain, such as the amygdala, hippocampus, hypothalamus, and brainstem nuclei like the locus coeruleus, nucleus basalis of Meynert, and dorsal motor nucleus of the vagus nerve. They may also appear in the neocortex and amygdala in some cases of PD. Research by Braak and Tredici further revealed that Lewy bodies can extend beyond the central nervous system (CNS) to peripheral and enteric nervous systems, suggesting a broader involvement of these aggregates in PD pathology.

In addition to alpha-synuclein, Lewy bodies are composed of other proteins such as tau, ubiquitin, and neurofilaments, which may contribute to their formation and stability [25]. Other proteins, including 14-3-3, DJ-1, parkin, and LRRK2, have also been detected in Lewy bodies, though their precise roles remain unclear and warrant further investigation [25, 26]. Understanding the function of these proteins within Lewy bodies, as well as their contributions to the pathogenesis of neurodegenerative disorders like PD, is critical for developing potential therapeutic interventions targeting this molecular pathology.

 

Repurposed drugs for PD treatment- results

 

  • Immunomodulatory and anti-neurodegenerative therapies

Abelson tyrosine kinase inhibitors

Abelson Tyrosine Kinase (c-Abl): Abelson tyrosine kinase (c-Abl) is a non-receptor tyrosine kinase crucial for cellular stress response. Studies on animal models of Parkinson's disease (PD) suggest that the activation of c-Abl contributes to the accumulation of α-Synuclein (α-Syn) and neuronal degradation, making c-Abl a potential target for disease-modifying therapies [27].

Imatinib, the first identified c-Abl inhibitor, has been used successfully in the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stromal tumors. Research in MPTP-induced mouse models of PD demonstrated the neuroprotective effects of Imatinib. Administering 30 mg/kg of Imatinib significantly reduced c-Abl tyrosine phosphorylation and protected dopaminergic neurons from degeneration [28].

Nilotinib is a second-generation c-Abl inhibitor with higher selectivity and better brain penetration compared to other inhibitors. Several clinical trials have assessed its efficacy in PD patients. In a phase 2, double-blind, placebo-controlled study with 63 participants, nilotinib was shown to be safe with no significant adverse effects. However, no meaningful clinical improvements in motor symptoms were observed [29, 30]. Another study confirmed nilotinib's safety but did not show significant motor or non-motor outcome improvements compared to the placebo group [31]. Nevertheless, nilotinib has been shown to alter dopamine metabolism by increasing the levels of DOPAC and homovanillic acid (HVA), indicating potential neurochemical effects that warrant further research [31].

Sargramostim

Sargramostim is a recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) that stimulates immune function by activating neutrophils, macrophages, and myeloid dendritic cells. Given the involvement of mitochondrial and peripheral immune dysfunction in PD, sargramostim has emerged as a potential long-term therapeutic option [32, 33]. Sargramostim was well tolerated in Parkinson's disease (PD) patients, according to a phase 1 randomised, placebo-controlled research. Adverse events included injection site reactions and mild bone discomfort [34]. In addition, sargramostim increased regulatory T-cell (Treg) subsets and improved MDS-UPDRS Part III scores after six to eight weeks of treatment. A subsequent phase 1b study with reduced sargramostim dosing (3 mg/kg/day) showed fewer adverse events without worsening motor symptoms, though larger studies are necessary to determine its therapeutic efficacy [35].

Rapamycin (Sirolimus)

Rapamycin, an mTOR (mammalian target of rapamycin) inhibitor, has been used as an immunosuppressant to prevent organ transplant rejection. In PD models, mTOR inhibition by rapamycin has been shown to activate autophagy, which helps clear α-Syn aggregates, reduce oxidative stress, and alleviate dopaminergic neuronal damage [36]. Studies on mice with parkin and PINK1 mutations indicate that rapamycin improves PD-related pathology by reducing muscle and mitochondrial degeneration [37]. However, more human trials are required to validate these results and assess rapamycin's therapeutic potential in individuals with Parkinson's disease.

Isoalantolactone

Isoalantolactone is a bioactive sesquiterpene lactone known for its anti-inflammatory and anti-tumor properties. Research has shown that IAL can prevent Amyloid β-induced toxicity and ameliorate MPTP-induced PD symptoms in mouse models [38, 39]. The neuroprotective effects of IAL are thought to be mediated through its activation of antioxidant pathways, specifically by stimulating the nuclear factor erythroid 2–related factor 2 (Nrf2) signaling pathway [40]. IAL treatment has also been shown to preserve dopaminergic neurons and reduce neuroinflammation, making it a promising candidate for PD treatment. However, further research is needed to elucidate its molecular mechanisms and therapeutic potential.

Interferon beta

IFN-β is a polypeptide drug widely used in the treatment of relapsing multiple sclerosis (MS). Recent studies indicate that IFN-β can reduce neuroinflammation and prevent neurodegeneration in PD models. IFN-β has been shown to promote α-Syn degradation and protect dopaminergic neurons by modulating mitochondrial dynamics through the STAT5-PGAM5-Drp1 pathway [41, 42]. In vivo models of PD have demonstrated that IFN-β prevents neuronal loss and oxidative damage. However, more research is needed to fully understand the neuroprotective mechanisms of IFN-β and its potential for PD therapy.

 

  • Cardiological and metabolic (anti-diabetic) drugs

Glucagon-like peptide 1 (GLP-1) agonists

Exenatide, a GLP-1 agonist, has emerged as one of the most studied drugs for potential repurposing in Parkinson's disease (PD) treatment. An open-label study showed a clinically significant improvement in both motor and cognitive symptoms in patients with moderate PD, with a mean improvement of 2.7 in the MDS-UPDRS scale compared to a decline of 2.2 in the control group (p = 0.037). Weight loss was the only notable adverse effect [43, 44]. Exenatide also showed the potential to slow down disease progression, as demonstrated in another clinical trial, where participants exhibited a mean improvement of 1.0 in MDS-UPDRS after 60 weeks of treatment (95% CI = -2.6 to 0.7) [45, 46]. Exenatide is currently completing phase III trials, and more research is being done on its neuroprotective, anti-apoptotic, anti-inflammatory, and antioxidative qualities [47]. Other GLP-1 agonists, including liraglutide and lixisenatide, are in phase II trials [48]. Semaglutide has shown potential by improving motor dysfunction, reducing α-Syn aggregation, and increasing glial cell line-derived neurotrophic factor (GDNF) expression in PD mouse models [43].

Insulin

The relationship between type 2 diabetes mellitus (T2DM) and PD has been recognized since the 1960s. A meta-analysis of seven population-based cohort studies reported a 38% increased risk of developing PD among diabetic patients [49, 50]. Studies have shown widespread insulin resistance and impaired insulin signaling in the brains of PD patients [47]. Observational studies indicate that PD patients have lower fasting plasma insulin levels and a higher fasting plasma amylin/fasting plasma insulin ratio (FPAIR), with FPAIR showing a modest correlation with non-motor symptoms (NMSS scale) [51]. Insulin has neuroprotective effects through the PI3K pathway, which may protect dopaminergic neurons from the harmful effects of hyperglycemia [52]. Research on intranasal insulin in rats has demonstrated encouraging outcomes in terms of promoting neurogenesis and warding off inflammation and reactive oxygen species [53]. Nevertheless, intranasal insulin did not show appreciable functional or cognitive advantages in phase II/III trials for Alzheimer's disease and moderate cognitive impairment [54].

Statins

Among statins, simvastatin has garnered the most attention due to its superior blood-brain barrier permeability compared to other statins like pravastatin and rosuvastatin. Preclinical studies in PD mouse models (6-OHDA and MPTP-induced) demonstrated simvastatin's neuroprotective effects [55]. Although cohort studies suggested that simvastatin may reduce PD risk, other retrospective case-control studies provided conflicting results [56]. A randomized controlled trial (RCT) in the UK enrolled 235 patients to assess simvastatin’s disease-modifying potential in PD. Despite the trial’s rigorous design, the results did not support simvastatin as a disease-modifying agent, and further trials were not pursued [57].

Metformin

Metformin, a widely used antidiabetic drug, has shown promising neuroprotective effects in vitro and in vivo. These include the inhibition of α-Syn phosphorylation and aggregation, the alleviation of oxidative stress, prevention of mitochondrial dysfunction, modulation of autophagy through the AMPK pathway, and inhibition of glial cell hyperactivation [58, 59]. Despite these promising preclinical findings, recent meta-analyses suggest that metformin use in humans does not correlate with reduced PD risk and may even increase the risk, particularly in monotherapy [60]. Issues with metformin’s bioavailability in the brain and potential adverse effects from long-term use may explain these contradictions. New stratification criteria for identifying PD patients who could benefit from metformin are being explored, including studies on patients with idiopathic REM sleep behavior disorder, a group at high risk for PD [61, 62].

Sodium-glucose cotransporter-2 (SGLT2) inhibitors

The pathogenesis of both PD and T2DM shares mechanisms such as mitochondrial dysfunction and oxidative stress. SGLT2 inhibitors (flozins) may offer neuroprotective effects through their glucose excretion properties, lowering glycated hemoglobin, and reducing ROS production by inhibiting NADPH oxidase activity. These actions protect mitochondrial function and reduce inflammation [63]. In a murine model of PD, dapagliflozin improved motor dysfunction, reduced oxidative stress, and attenuated ROS-dependent apoptosis [64]. A large population-based study comparing SGLT2 inhibitors with dipeptidyl peptidase-4 inhibitors (DPP4i) found a lower risk of PD in the SGLT2 group (HR = 0.28; 95% CI: 0.09 to 0.91; p = 0.0349) [65].

Deferiprone

Ferroptosis, an iron-dependent form of cell death, has been implicated in PD pathology, with increased iron accumulation observed in the brains of PD patients. Deferiprone, an iron chelator, has shown efficacy in reducing oxidative stress, improving motor activity, and preserving dopamine levels in preclinical PD models [55, 66]. Positive results from small-scale human studies also prompted the start of larger RCTs, such the 372 participant FAIR PARK II experiment. Regretfully, further findings revealed that deferiprone was linked to worse parkinsonism scores among PD patients who had not yet started dopaminergic therapies, undermining the drug's potential as a therapeutic intervention [67, 68].

Antihypertensive drugs

Calcium channel blockers (CCBs)

Epidemiological studies suggest that CCBs, particularly isradipine, may reduce PD risk. However, the STEADY-PD phase III RCT, involving 336 patients, failed to demonstrate isradipine’s efficacy in slowing PD progression [56, 69]. While a modest impact on delaying the need for antiparkinsonian treatments was observed, the study highlighted dosage limitations as a potential issue [70]. Computational analysis using IBM Watson identified nifedipine as another potential candidate, though it has been associated with parkinsonism syndromes in some reports [71, 72].

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs)

Preclinical evidence supports the role of the renin-angiotensin system (RAS) in neuroinflammation and oxidative stress in PD, making ACE inhibitors and ARBs attractive therapeutic options. Studies have shown that drugs such as captopril and losartan can enhance L-DOPA effects without inducing dyskinesias and reduce PD risk in clinical populations [56, 73-77]. However, the quality of evidence remains low, and further trials are necessary to validate these findings [72].

 

  • Anti-infective drugs in parkinson's disease (PD) therapy

Minocycline

Minocycline, a second-generation tetracycline antibiotic, exhibits efficacy against both gram-positive and gram-negative bacteria. Owing to its lipophilicity, it can easily cross the blood-brain barrier (BBB) and accumulate in the cerebrospinal fluid (CSF) and central nervous system (CNS). This allows minocycline to be used in the treatment of CNS diseases, including PD. Minocycline exerts neuroprotective effects by inhibiting proinflammatory molecule production, reducing mitochondrial dysfunction, and preventing microglial activation, which are key processes in the etiopathogenesis of PD [78]. Preclinical studies in rotenone-induced PD rat models have demonstrated that minocycline can slightly alleviate motor deficits, although it has not shown significant improvements in motor function in clinical studies involving early PD patients [79].

Doxycycline

Doxycycline, another second-generation tetracycline antibiotic, is commonly used for bacterial infections. Recent studies highlight its ability to inhibit α-Syn aggregation and reduce mitochondrial-derived reactive oxygen species (ROS) [80]. In an experiment involving human α-Syn A53T transgenic mice, doxycycline treatment (10 mg/kg daily for 30 days) significantly improved motor function, including gait stability and muscle strength [81]. This suggests that doxycycline could be a potential therapeutic option for addressing both motor symptoms and neuropathological changes in PD. A randomized, double-blind, placebo-controlled trial is currently recruiting PD patients to further assess doxycycline's effects on motor performance and cognitive function in individuals receiving levodopa (NCT05492019).

Geldanamycin

Geldanamycin is an ansamycin antibiotic originally developed as an anticancer drug. It inhibits the function of Heat Shock Protein 90 (Hsp90) and upregulates Heat Shock Protein 70 (Hsp70). Hsp70 is known to prevent α-Syn misfolding and reduce amyloid aggregation [82]. Inhibition of Hsp90 by geldanamycin has shown protective effects against MPTP-induced dopaminergic neurotoxicity in PD models, due to the induction of Hsp70, which counters neurotoxicity and mitochondrial stress [83]. Despite these promising results, the toxicity of geldanamycin limits its clinical application. However, structural analogs of geldanamycin, such as 17-AAG, 17-DMAG, IPI-493, and retaspimycin, are currently being evaluated in clinical trials as potential treatments for PD [84].

Rifampicin

Rifampicin, an ansamycin antibiotic primarily used to treat mycobacterial infections, has demonstrated anti-inflammatory, anti-aggregating, and antioxidant properties, making it a potential therapeutic candidate for neurological disorders like PD [84]. Rifampicin has been shown in experimental tests to lessen neuroinflammation and neurodegeneration brought on by fibrillary aggregates of α-Syn [85]. Rifampicin reduced apoptosis in zebrafish models of PD caused by rotenone through the reduction of pro-inflammatory cytokines such as IL-1β and IL-6 and the mitigation of mitochondrial oxidative stress [86]. These results suggest that rifampicin could modulate neuroinflammation and reduce mitochondrial dysfunction in PD, though further evaluation in clinical settings is needed.

Ceftriaxone

Ceftriaxone, a third-generation cephalosporin antibiotic, can cross the BBB and has shown neuroprotective effects in CNS disorders by upregulating excitatory amino acid transporter 2 (GLT-1) expression [87]. Chronic administration of ceftriaxone (200 mg/kg) in MPTP-induced PD rat models resulted in significant improvements in motor function and reduced oxidative damage. Furthermore, ceftriaxone downregulated neuroinflammation markers such as glial fibrillary acidic protein (GFAP) and Toll-like receptor 4 (TLR4) while reducing pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) [88]. A phase II randomized, double-blind, placebo-controlled trial is underway to assess the efficacy and safety of ceftriaxone in patients with PD dementia (NCT03413384).

Niclosamide

Niclosamide, an antihelminthic drug, has been recognized for its ability to modulate mitochondrial phosphorylation and influence various signaling pathways, including mTOR and JAK/STAT3 [89]. Niclosamide has shown promise in activating PINK1, a kinase involved in protecting against mitochondrial dysfunction, which is particularly relevant in autosomal recessive PD [90]. Niclosamide also promotes neurite growth in dopaminergic neurons and protects against α-Syn-induced neurodegeneration through the BMP-Smad pathway [91]. Although niclosamide shows potential as a neuroprotective agent, further research in in vivo PD models is required to determine its effectiveness and safety.

CONCLUSION

This study highlights the potential of repurposed drugs for Parkinson's disease, focusing on immunomodulatory, cardiometabolic, and anti-infective agents. Immunomodulators like c-Abl inhibitors (imatinib, nilotinib) show neuroprotective effects by targeting α-Syn aggregation and cellular stress pathways, though clinical efficacy remains inconclusive. Cardiometabolic drugs, particularly GLP-1 agonists such as exenatide, demonstrate promising results in motor and cognitive symptom improvement, with potential disease-modifying effects. Anti-infective agents (minocycline, doxycycline, rifampicin) offer neuroprotection through anti-inflammatory and anti-aggregating actions, though clinical translation is limited by mixed results and toxicity concerns.

While these drugs offer promising therapeutic strategies, further large-scale trials are necessary to confirm their efficacy and safety. A deeper understanding of their molecular mechanisms in PD could guide the development of optimized treatment approaches.

ACKNOWLEDGMENTS : None

CONFLICT OF INTEREST : None

FINANCIAL SUPPORT : None

ETHICS STATEMENT : None

References
  1. Church FC. Treatment options for motor and non-motor symptoms of Parkinson’s disease. Biomolecules. 2021;11(4):612.
  2. DeMaagd G, Ashok P. Parkinson’s disease and its management part 1: Disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. BMJ. 2015;308(6923):281.
  3. Hermanowicz N, Jones SA, Hauser RA. Impact of non-motor symptoms in Parkinson's disease: A PMDAlliance survey. Neuropsychiatr Dis Treat. 2019;15:2205-12. doi:10.2147/NDT.S213917
  4. Cosentino G, Avenali M, Schindler A, Pizzorni N, Montomoli C, Abbruzzese G, et al. A multinational consensus on dysphagia in Parkinson’s disease: Screening, diagnosis and prognostic value. J Neurol. 2022;269(3):1335-52.
  5. Mantovani S, Smith SS, Gordon R, O’Sullivan JD. An overview of sleep and circadian dysfunction in Parkinson’s disease. J Sleep Res. 2018;27(3):1-22.
  6. Tan AH, Lim SY, Chong KK, A Manap MAA, Hor JW, Lim JL, et al. Probiotics for constipation in Parkinson disease: A randomized placebo-controlled study. Neurology. 2021;96(5):772-82.
  7. National Institute of Neurological Disorders and Stroke. Parkinson’s disease: Challenges, progress, and promise. 2023.
  8. Marras C, Beck JC, Bower JH, Roberts E, Ritz B, Ross GW, et al. Prevalence of Parkinson’s disease across North America. npj Park Dis. 2018;4(1):1-7.
  9. Willis AW, Roberts E, Beck JC, Fiske B, Ross W, Savica R, et al. Incidence of Parkinson disease in North America. npj Park Dis. 2022;8(1):1-12.
  10. Rizek P, Kumar N, Mandar SJ. Diagnosis and treatment of Parkinson. Acad Med Ont Southwest. 2016;188(16):1157-65.
  11. Ray Dorsey E, Elbaz A, Nichols E, Abd-Allah F, Abdelalim A, Adsuar JC, et al. Global, regional, and national burden of Parkinson’s disease, 1990–2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2018;17(11):939-53.
  12. Gómez-Benito M, Granado N, García-Sanz P, Michel A, Dumoulin M, Moratalla R. Modeling Parkinson’s disease with the alpha-synuclein protein. Front Pharmacol. 2020;11:1-15.
  13. Ben-Joseph A, Marshall CR, Lees AJ, Noyce AJ. Ethnic variation in the manifestation of Parkinson’s disease: A narrative review. J Parkinsons Dis. 2020;10(1):31-45.
  14. Hu S, Tan J, Qin L, Lv L, Yan W, Zhang H, et al. Molecular chaperones and Parkinson’s disease. Neurobiol Dis. 2021;160:105527.
  15. Sulzer D, Edwards RH. The physiological role of α-synuclein and its relationship to Parkinson’s Disease. J Neurochem. 2019;150(5):475-86.
  16. Delenclos M, Burgess JD, Lamprokostopoulou A, Outeiro TF, Vekrellis K, McLean PJ. Cellular models of alpha-Synuclein toxicity and aggregation. J Neurochem. 2019;150(5):566-76.
  17. Puspita L, Chung SY, Shim JW. Oxidative stress and cellular pathologies in Parkinson’s disease. Mol Brain. 2017;10(1):1-12.
  18. Lazarevic V, Yang Y, Paslawski W, Svenningsson P. α-Synuclein induced cholesterol lowering increases tonic and reduces depolarization-evoked synaptic vesicle recycling and glutamate release. npj Park Dis. 2022;8(1):1-10.
  19. Morris HR, Spillantini MG, Sue CM, Williams-Gray CH. The pathogenesis of Parkinson's disease. Lancet. 2024;403(10423):293-304. doi:10.1016/S0140-6736(23)01478-2
  20. Tofaris GK. Initiation and progression of α-synuclein pathology in Parkinson's disease. Cell Mol Life Sci. 2022;79(4):210. doi:10.1007/s00018-022-04240-2.
  21. Chong W, Jiménez J, McIIvin M, Saito MA, Kwakye GF. α-Synuclein enhances cadmium uptake and neurotoxicity via oxidative stress and caspase activated cell death mechanisms in a dopaminergic cell model of Parkinson’s disease. Neurotox Res. 2017;32(2):231-46.
  22. Hu Q, Hong M, Huang M, Gong Q, Zhang X, Uversky VN, et al. Age-dependent aggregation of α-synuclein in the nervous system of gut-brain axis is associated with caspase-1 activation. Metab Brain Dis. 2022;37(5):1669-81.
  23. Menšíková K, Matěj R, Colosimo C, Rosales R, Tučková L, Ehrmann J, et al. Lewy body disease or diseases with Lewy bodies? npj Park Dis. 2022;8(1):1-12.
  24. Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson’s disease. npj Park Dis. 2022;19(2):170-8.
  25. Fares MB, Jagannath S, Lashuel HA. Reverse engineering lewy bodies: How far have we come and how far can we go? Nat Rev Neurosci. 2021;22(2):111-31.
  26. Giusto E, Yacoubian TA, Greggio E, Civiero L. Pathways to Parkinson’s disease: A spotlight on 14-3-3 proteins. npj Park Dis. 2021;7(1):1-10.
  27. Werner MH, Olanow CW. Parkinson's disease modification through Abl kinase inhibition: An opportunity. Mov Disord. 2022;37(1):6-15. doi:10.1002/mds.28858
  28. Wu R, Chen H, Ma J, He Q, Huang Q, Liu Q, et al. C-Abl-p38α signaling plays an important role in MPTP-induced neuronal death. Cell Death Differ. 2016;23(3):542-52.
  29. De Santis S, Monaldi C, Mancini M, Bruno S, Cavo M, Soverini S. Overcoming resistance to kinase inhibitors: The paradigm of chronic myeloid leukemia. Onco Targets Ther. 2022;15:103-16. doi:10.2147/OTT.S289306
  30. Pagan FL, Wilmarth B, Torres-Yaghi Y, Hebron ML, Mulki S, Ferrante D, et al. Long-term safety and clinical effects of nilotinib in Parkinson’s disease. Mov Disord. 2021;36(3):740-9.
  31. Pagan FL, Hebron ML, Wilmarth B, Torres-Yaghi Y, Lawler A, Mundel EE, et al. Nilotinib effects on safety, tolerability, and potential biomarkers in Parkinson disease: A phase 2 randomized clinical trial. JAMA Neurol. 2020;77(3):309-17.
  32. Pagan FL, Hebron ML, Wilmarth B, Torres-Yaghi Y, Lawler A, Mundel EE, et al. Pharmacokinetics and pharmacodynamics of a single dose Nilotinib in individuals with Parkinson’s disease. Pharmacol Res Perspect. 2019;7(2):1-10.
  33. Waller EK. The role of sargramostim (rhGM-CSF) as immunotherapy. Oncologist. 2007;12(S2):22-6.
  34. Gendelman HE, Zhang Y, Santamaria P, Olson KE, Schutt CR, Bhatti D, et al. Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial. npj Parkinsons Dis. 2017;3(1):1-10.
  35. Olson KE, Namminga KL, Lu Y, Schwab AD, Thurston MJ, Abdelmoaty MM, et al. Safety, tolerability, and immune-biomarker profiling for year-long sargramostim treatment of Parkinson’s disease. EBioMedicine. 2021;67:1-12.
  36. Lan AP, Chen J, Zhao Y, Chai Z, Hu Y. mTOR signaling in Parkinson’s disease. NeuroMolecular Med. 2017;19(2):1-12.
  37. Zhang G, Yin L, Luo Z, Chen X, He Y, Yu X, et al. Effects and potential mechanisms of rapamycin on MPTP-induced acute Parkinson’s disease in mice. Ann Palliat Med. 2021;10(3):2889-97.
  38. Kalola J, Shah R, Patel A, Lahiri SK, Shah MB. Anti-inflammatory and immunomodulatory activities of Inula cappa roots (Compositae). J Complement Integr Med. 2017;14(3):1-10.
  39. Seo JY, Lim SS, Kim J, Lee KW, Kim JS. Alantolactone and isoalantolactone prevent amyloid β25–35-induced toxicity in mouse cortical neurons and scopolamine-induced cognitive impairment in mice. Phytother Res. 2017;31(5):801-11.
  40. He D, Liu Y, Li J, Wang H, Ye B, He Y, et al. Isoalantolactone (IAL) regulates neuro-inflammation and neuronal apoptosis to curb pathology of Parkinson’s disease. Cells. 2022;11(18):1-15.
  41. Ejlerskov P, Hultberg JG, Wang JY, Carlsson R, Ambjørn M, Kuss M, et al. Lack of neuronal IFN-β-IFNAR causes lewy body- and Parkinson’s disease-like dementia. Cell. 2015;163(2):324-39.
  42. Tresse E, Riera‐Ponsati L, Jaberi E, Sew WQG, Ruscher K, Issazadeh‐Navikas S. IFN‐β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1. EMBO J. 2021;40(11):1-12.
  43. Hernández-Parra H, Cortés H, Avalos-Fuentes JA, del Prado-Audelo M, Florán B, Leyva-Gómez G, et al. Repositioning of drugs for Parkinson’s disease and pharmaceutical nanotechnology tools for their optimization. J Nanobiotechnology. 2022;20(1):1-15.
  44. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013;123(6):2730-40.
  45. Kim DS, Choi H, Wang Y, Luo Y, Hoffer BJ, Greig NH. A new treatment strategy for Parkinson’s disease through the gut-brain axis: The glucagon-like peptide-1 receptor pathway. Cell Transplant. 2017;26(3):438-49.
  46. Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, et al. Exenatide once weekly versus placebo in Parkinson’s disease: A randomized, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664-75.
  47. Nowell J, Blunt E, Edison P. Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease. Mol Psychiatry. 2022;27(3):1472-84.
  48. Brundin P, Wyse RK. The linked clinical trials initiative (LCT) for Parkinson’s disease. Eur J Neurosci. 2019;49(3):307-15.
  49. de Iuliis A, Montinaro E, Fatati G, Plebani M, Colosimo C. Diabetes mellitus and Parkinson’s disease: Dangerous liaisons between insulin and dopamine. Neural Regen Res. 2022;17(7):1350-6.
  50. Yue X, Li H, Yan H, Zhang P, Chang L, Li T. Risk of Parkinson disease in diabetes mellitus: An updated meta-analysis of population-based cohort studies. Medicine. 2016;95(18):1-9.
  51. Sánchez-Gómez A, Alcarraz-Vizán G, Fernández M, Fernández R, Ezquerra M, Cámara A, et al. Peripheral insulin and amylin levels in Parkinson’s disease. Parkinsonism Relat Disord. 2020;72:1-5.
  52. Labandeira C, Fraga-Bau A, Arias Ron D, Alvarez-Rodriguez E, Vicente-Alba P, Lago-Garma J, et al. Parkinson’s disease and diabetes mellitus: Common mechanisms and treatment repurposing. Neural Regen Res. 2022;17(1):1-10.
  53. Cheong JLY, de Pablo-Fernandez E, Foltynie T, Noyce AJ. The association between type 2 diabetes mellitus and Parkinson’s disease. J Parkinsons Dis. 2020;10(3):775-89.
  54. Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA, et al. Safety, efficacy, and feasibility of intranasal insulin for the treatment of mild cognitive impairment and Alzheimer disease dementia: A randomized clinical trial. JAMA Neurol. 2020;77(9):1099-110.
  55. Kakkar AK, Singh H, Medhi B. Old wines in new bottles: Repurposing opportunities for Parkinson’s disease. Eur J Pharmacol. 2018;837:90-104.
  56. Tang Y, Yang K, Zhao J, Liang X, Wang J. Evidence of repurposing drugs and identifying contraindications from real world study in Parkinson’s disease. ACS Chem Neurosci. 2019;10(9):3948-58.
  57. Stevens KN, Creanor S, Jeffery A, Whone A, Zajicek J, Foggo A, et al. Evaluation of simvastatin as a disease-modifying treatment for patients with Parkinson disease. JAMA Neurol. 2022;79(1):71-81.
  58. Paudel YN, Angelopoulou E, Piperi C, Shaikh MF, Othman I. Emerging neuroprotective effect of metformin in Parkinson’s disease: A molecular crosstalk. Pharmacol Res. 2020;152:104593.
  59. Cardoso S, Moreira PI. Antidiabetic drugs for Alzheimer’s and Parkinson’s diseases: Repurposing insulin, metformin, and thiazolidinediones. Int Rev Neurobiol. 2020;155:37-72.
  60. Ping F, Jiang N, Li Y. Association between metformin and neurodegenerative diseases of observational studies: Systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2020;8(1):1-9.
  61. Agostini F, Masato A, Bubacco L, Bisaglia M. Metformin repurposing for Parkinson disease therapy: Opportunities and challenges. Int J Mol Sci. 2022;23(2):1-19.
  62. Sportelli C, Urso D, Jenner P, Chaudhuri KR. Metformin as a potential neuroprotective agent in prodromal Parkinson’s disease-Viewpoint. Front Neurol. 2020;11:1-10.
  63. Lin KJ, Wang TJ, Chen SD, Lin KL, Liou CW, Lan MY, et al. Two birds one stone: The neuroprotective effect of antidiabetic agents on Parkinson disease—Focus on sodium-glucose cotransporter 2 (SGLT2) inhibitors. Antioxidants. 2021;10(4):1-10.
  64. Arab HH, Safar MM, Shahin NN. Targeting ROS-dependent AKT/GSK-3β/NF-κB and DJ-1/Nrf2 pathways by dapagliflozin attenuates neuronal injury and motor dysfunction in a rotenone-induced Parkinson’s disease rat model. ACS Chem Neurosci. 2021;12(4):674-86.
  65. Mui JV, Zhou J, Lee S, Leung KSK, Lee TTL, Chou OHI, et al. Sodium-glucose cotransporter 2 (SGLT2) inhibitors vs. dipeptidyl peptidase-4 (DPP4) inhibitors for new-onset dementia: A propensity score-matched population-based study with competing risk analysis. Front Cardiovasc Med. 2021;8:1-11.
  66. Mahoney-Sánchez L, Bouchaoui H, Ayton S, Devos D, Duce JA, Devedjian JC. Ferroptosis and its potential role in the physiopathology of Parkinson’s disease. Prog Neurobiol. 2021;196:1-15.
  67. Hung AY, Schwarzschild MA. Approaches to disease modification for Parkinson’s disease: Clinical trials and lessons learned. Neurotherapeutics. 2020;17(2):436-48.
  68. Devos D, Labreuche J, Rascol O, Corvol JC, Duhamel A, Guyon Delannoy P, et al. Trial of deferiprone in Parkinson’s disease. N Engl J Med. 2022;386(13):1257-66.
  69. Simuni T, Chang Y, Fernandopulle N, Nwabuobi L, Lee H. Isradipine versus placebo in early Parkinson disease: A randomized trial. Ann Intern Med. 2020;172(9):591-8.
  70. Venuto CS, Yang L, Javidnia M, Oakes D, Surmeier DJ, Simuni T. Isradipine plasma pharmacokinetics and exposure–response in early Parkinson’s disease. Ann Clin Transl Neurol. 2021;8(9):1849-59.
  71. Visanji NP, Madan P, Lacoste AMB, Buleje I, Han Y, Spangler S, et al. Using artificial intelligence to identify anti-hypertensives as possible disease-modifying agents in Parkinson’s disease. Pharmacoepidemiol Drug Saf. 2021;30(9):1229-36.
  72. Tulbă D, Avasilichioaiei M, Dima N, Crăciun L, Bălănescu P, Buzea A, et al. Shared molecular targets in Parkinson’s disease and arterial hypertension: A systematic review. Neural Regen Res. 2022;17(1):1-10.
  73. Perez-Lloret S, Otero-Losada M, Toblli JE, Capani F. Renin-angiotensin system as a potential target for new therapeutic approaches in Parkinson’s disease. Expert Opin Investig Drugs. 2017;26(11):1285-94.
  74. Contaldi E, Magistrelli L, Milner A, Cosentino M, Marino F, Comi C. Potential protective role of ACE-inhibitors and AT1 receptor blockers against levodopa-induced dyskinesias: A retrospective case-control study. Neural Regen Res. 2021;16(12):2443-51.
  75. Udovin L, Otero-Losada M, Bordet S, Chevalier G, Quarracino C, Capani F, et al. Effects of angiotensin type 1 receptor antagonists on Parkinson’s disease progression: An exploratory study in the PPMI database. Parkinsonism Relat Disord. 2021;91:1-8.
  76. Laudisio A, lo Monaco MR, Silveri MC, Bentivoglio AR, Vetrano DL, Pisciotta MS, et al. Use of ACE-inhibitors and falls in patients with Parkinson’s disease. Gait Posture. 2017;56:114-9.
  77. Jo Y, Kim S, Ye BS, Lee E, Yu YM. Protective effect of renin-angiotensin system inhibitors on Parkinson’s disease: A nationwide cohort study. Front Pharmacol. 2022;13:1-12.
  78. Bortolanza M, Nascimento GC, Socias SB, Ploper D, Chehín RN, Raisman-Vozari R, et al. Tetracycline repurposing in neurodegeneration: Focus on Parkinson’s disease. J Neural Transm. 2018;125(12):1403-15.
  79. Sun C, Wang Y, Mo M, Song C, Wang X, Chen S, et al. Minocycline protects against rotenone-induced neurotoxicity correlating with upregulation of Nurr1 in a Parkinson’s disease rat model. Biomed Res Int. 2019;2019:1-10.
  80. Dominguez-Meijide A, Parrales V, Vasili E, González-Lizárraga F, König A, Lázaro DF, et al. Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo. Neurobiol Dis. 2021;151:1-12.
  81. Vitola P, Artioli L, Leva S, Balducci C, Forloni G. Rifampicin and its derivative rifampicin quinone reduce microglial inflammatory responses and neurodegeneration induced in vitro by α-synuclein fibrillary aggregates. Cells. 2019;8(8):1-12.
  82. Erekat N, Al-Khatib A, Al-Jarrah M. Heat shock protein 90 is a potential therapeutic target for ameliorating skeletal muscle abnormalities in Parkinson’s disease. Neural Regen Res. 2014;9(6):616-21.
  83. Rane A, Rajagopalan S, Ahuja M, Thomas B, Chinta SJ, Andersen JK. Hsp90 Co-chaperone p23 contributes to dopaminergic mitochondrial stress via stabilization of PHD2: Implications for Parkinson’s disease. Neurotoxicology. 2018;65:166-73.
  84. Socias SB, González-Lizárraga F, Avila CL, Vera C, Acuña L, Sepulveda-Diaz JE, et al. Exploiting the therapeutic potential of ready-to-use drugs: Repurposing antibiotics against amyloid aggregation in neurodegenerative diseases. Prog Neurobiol. 2018;162:17-36.
  85. Acuña L, Hamadat S, Corbalán NS, González-lizárraga F, Dos-santos-pereira M, Rocca J, et al. Rifampicin and its derivative rifampicin quinone reduce microglial inflammatory responses and neurodegeneration induced in vitro by α-synuclein fibrillary aggregates. Cells. 2019;8(8):1-12.
  86. Yurtsever İ, Üstündağ ÜV, Ünal İ, Ateş PS, Emekli-Alturfan E. Rifampicin decreases neuroinflammation to maintain mitochondrial function and calcium homeostasis in rotenone-treated zebrafish. Drug Chem Toxicol. 2022;45(4):1544-51.
  87. Kaur B, Prakash A. Ceftriaxone attenuates glutamate-mediated neuro-inflammation and restores BDNF in MPTP model of Parkinson’s disease in rats. Pathophysiology. 2017;24(2):71-9.
  88. Zhou X, Lu J, Wei K, Wei J, Tian P, Yue M, et al. Neuroprotective effect of ceftriaxone on MPTP-induced Parkinson’s disease mouse model by regulating inflammation and intestinal microbiota. Oxid Med Cell Longev. 2021;2021:1-12.
  89. Kadri H, Lambourne OA, Mehellou Y. Niclosamide, a drug with many (re)purposes. ChemMedChem. 2018;13(11):1088-91.
  90. Barini E, Miccoli A, Tinarelli F, Mulholland K, Kadri H, Khanim F, et al. The anthelmintic drug niclosamide and its analogues activate the Parkinson’s disease-associated protein kinase PINK1. ChemBioChem. 2018;19(5):425-9.
  91. Goulding SR, Lévesque M, Sullivan AM, Collins LM, O’Keeffe GW. Quinacrine and Niclosamide promote neurite growth in midbrain dopaminergic neurons through the canonical BMP-Smad pathway and protect against neurotoxin and α-synuclein-induced neurodegeneration. Mol Neurobiol. 2021;58(7):3405-16.

 


How to cite this article
Vancouver
Lastovetskyi I, Cytlau B, Marczyk Ł, Zdrojewska K, Łach A, Krupa J, et al. Modern Pharmacological Treatment of Parkinson's Disease : Reviving Known Drugs and New Perspectives. Int J Pharm Res Allied Sci. 2024;13(4):29-39. https://doi.org/10.51847/TWysUbD6PP
APA
Lastovetskyi, I., Cytlau, B., Marczyk, Ł., Zdrojewska, K., Łach, A., Krupa, J., Lorkowska-Zawicka, B., & Giżycka, B. B. (2024). Modern Pharmacological Treatment of Parkinson's Disease : Reviving Known Drugs and New Perspectives. International Journal of Pharmaceutical Research and Allied Sciences, 13(4), 29-39. https://doi.org/10.51847/TWysUbD6PP
Related articles:
Most viewed articles:
Issue 1 Volume 14 (2025)