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

IF 2.5 4区医学 Q2 NEUROSCIENCES

Purinergic Signalling Pub Date : 2026-05-14 DOI:10.1007/s11302-026-10160-8

Mokhtar Rejili, Hayder M Al-Kuraishy, Ali I Al-Gareeb, Ali K Albuhadily, Majid S Jabir, Mustafa M Shokr, Gaber El-Saber Batiha

{"title":"Purinergic modulation in Parkinson's disease: the dual role of istradefylline in motor and cognitive outcomes.","authors":"Mokhtar Rejili, Hayder M Al-Kuraishy, Ali I Al-Gareeb, Ali K Albuhadily, Majid S Jabir, Mustafa M Shokr, Gaber El-Saber Batiha","doi":"10.1007/s11302-026-10160-8","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 3","pages":""},"PeriodicalIF":2.5000,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13176427/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Purinergic Signalling","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11302-026-10160-8","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

帕金森氏病的嘌呤能调节：司他茶碱在运动和认知结果中的双重作用。

isstradefylline是一种选择性腺苷2A受体（A2AR）拮抗剂，于2019年被批准作为辅助治疗，以减少帕金森病（PD）患者的“OFF”期。这篇全面的综述评估了其对帕金森病的双重影响，对比了运动症状管理中已建立的治疗效果和对认知安全的新关注。isstradefylline增强了多巴胺能在黑质致密部（SNpc）的传递，显著减少左旋多巴诱导的肌动症。除了运动控制外，它还通过减轻神经炎症、氧化应激和α -突触核蛋白诱导的神经毒性表现出神经保护潜力。然而，临床前证据表明了一个令人担忧的悖论：iststradefylline可能通过γ-分泌酶的过度活性和脑源性神经营养因子（BDNF）信号通路的破坏，促进淀粉样蛋白- β (a β)的积累，从而加剧认知能力下降。此外，其对d -天冬氨酸蛋白的抑制作用可能引发线粒体功能障碍和内质网应激，可能加速SNpc的神经退行性变。虽然iststradefylline仍然是一种稳定运动波动的有价值的非多巴胺能策略，但它对长期认知功能的影响需要仔细的临床考虑。了解这些相反作用背后的分子机制对于优化其使用和最小化PD患者的神经认知风险至关重要。未来的纵向试验对于阐明其长期安全性和改善疾病的潜力至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Purinergic Signalling 医学-神经科学

CiteScore

6.60

自引率

17.10%

发文量

审稿时长

6-12 weeks

期刊介绍： Nucleotides and nucleosides are primitive biological molecules that were utilized early in evolution both as intracellular energy sources and as extracellular signalling molecules. ATP was first identified as a neurotransmitter and later as a co-transmitter with all the established neurotransmitters in both peripheral and central nervous systems. Four subtypes of P1 (adenosine) receptors, 7 subtypes of P2X ion channel receptors and 8 subtypes of P2Y G protein-coupled receptors have currently been identified. Since P2 receptors were first cloned in the early 1990’s, there is clear evidence for the widespread distribution of both P1 and P2 receptor subtypes in neuronal and non-neuronal cells, including glial, immune, bone, muscle, endothelial, epithelial and endocrine cells.