Purinergic modulation in Parkinson’s disease: the dual role of istradefylline in motor and cognitive outcomes

Abstract

Istradefylline, a selective adenosine 2A receptor (A2AR) antagonist, was approved in 2019 as an adjuvant treatment to reduce “OFF” periods in Parkinson’s disease (PD) patients. This comprehensive review evaluates its dual impact on PD, contrasting established therapeutic benefits in motor symptom management with emerging concerns regarding cognitive safety. Istradefylline enhances dopaminergic transmission in the substantia nigra pars compacta (SNpc), significantly reducing L-DOPA-induced akinesia. Beyond motor control, it exhibits neuroprotective potential by mitigating neuroinflammation, oxidative stress, and alpha-synuclein-induced neurotoxicity. However, preclinical evidence suggests a concerning paradox: istradefylline may exacerbate cognitive decline by promoting amyloid-beta (Aβ) accumulation through the overactivity of γ-secretase and the disruption of brain-derived neurotrophic factor (BDNF) signaling pathways. Furthermore, its inhibitory effect on D-aspartate protein may trigger mitochondrial dysfunction and endoplasmic reticulum stress, potentially accelerating neurodegeneration in the SNpc. While istradefylline remains a valuable non-dopaminergic strategy for stabilizing motor fluctuations, its influence on long-term cognitive function necessitates careful clinical consideration. Understanding the molecular mechanisms behind these opposing effects is essential for optimizing its use and minimizing neurocognitive risks in PD patients. Future longitudinal trials are vital to clarify its long-term safety profile and disease-modifying potential.