Therapeutics candidates and repurposing strategies to target parkinson's disease pathology: current evidence and future directions
Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide, affecting over 8.5 million individuals globally. Its pathophysiology is multifactorial, encompassing progressive loss of dopaminergic neurons in the substantia nigra, accumulation of misfolded alpha-synuclein, mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired proteostasis. Despite decades of research, current treatments remain predominantly symptomatic, with levodopa and dopamine replacement therapies failing to halt neurodegeneration. Given the high cost and low success rate of de novo drug development, both repurposed approved drugs and mechanistically targeted investigational therapeutics have emerged as promising approaches as a strategically rational alternative that leverages established safety profiles, known pharmacokinetics, and abbreviated regulatory pathways. This review aimed to comprehensively examine the current evidence for repurposed drugs, clinically investigated therapeutic candidates, and repositioning strategies targeting the principal pathological hallmarks of Parkinson's disease: (1) alpha-synuclein aggregation and propagation, (2) oxidative stress, (3) neuroinflammation, (4) mitochondrial dysfunction, (5) lysosomal and proteasomal dysfunction, and (6) dopaminergic neurodegeneration. The review further sought to identify recurring translational challenges, propose mechanistic frameworks for rational combination therapy, and outline…
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