Adenosine 2A Receptor Antagonists for the Treatment of Motor Symptoms in Parkinson's Disease

Abstract

Background: Treatment of motor fluctuations in Parkinson's disease (PD) remains an unmet challenge. Adenosine 2A (A 2A ) receptors are located along the indirect pathway and represent a potential target to enhance L-3,4-dihydroxyphenylalanine (L-DOPA) antiparkinsonian action.Methods: This article summarizes the preclinical and clinical literature on A 2A antagonists in PD, with a specific focus on their effect on off time, on time, and dyskinesia. Findings: Several A 2A receptor antagonists have been tested in preclinical studies and clinical trials. In preclinical studies, A 2A antagonists enhanced L-DOPA antiparkinsonian action without exacerbating dyskinesia, but A 2A antagonists were generally administered in combination with a subthreshold dose of L-DOPA, which is different to the paradigms used in clinical trials, where A 2A antagonists were usually added to an optimal antiparkinsonian regimen. In clinical settings, A 2A antagonists generally reduced duration of off time, by as much as 25% in some studies. The effect of on time duration is less clear, and in a few studies an exacerbation of dyskinesia was reported. Two

Role of Adenosine A2AReceptors in the Central Fatigue of Neurodegenerative Diseases

“…Caffeine (1,3,7-trimethylxantine) is the most consumed social drug in western society, and it is also the main ergogenic resource used by recreational, professional, and elite athletes. [36][37][38][39][40][41][42][43][44] Caffeine delays fatigue during exercise and reduces rated perceived exertion. [197][198][199][200][201][202] Moreover, caffeine improves cognitive performance, 190,191,203 attention, vigilance tasks, 188 arousals, and alertness, and reduces mental fatigue.…”

“…35 Caffeine, a nonselective antagonist for adenosine A 1 receptor (A 1 R) and A 2A receptor (A 2A R), has a strong effect on reducing the perception of effort, making it the most used ergogenic resource for professional and elite athletes. [36][37][38][39][40][41][42][43][44] That is, blocking A 1 R and A 2A R by caffeine decreases fatigue in athletes. On the other hand, increased A 2A R density is involved in the neuropathology and symptoms of major neurodegenerative diseases, as fatigue in MS, 45 PD, 46 and AD.…”

“…113,114 Caffeine is the main ergogenic substance used by athletes. [36][37][38][39][40][41][42][43][44] The ergogenic mechanisms of caffeine are unknown, but they seem to be dependent on A 2A R in the central nervous system (CNS). Davis et al 115 abolished the ergogenic effects of caffeine on a treadmill using the intracerebroventricular adenosine agonist 5¢-N-ethylcarboxamidoadenosine (NECA, K i = 14 and 20 nM for A 1 R and A 2A R, respectively) in rats.…”

Pharmacological Insights into Levodopa‐induced Motor Fluctuations in Patients with Parkinson's Disease

“…The second example of a nondopaminergic hypothesis that was tested to treat motor fluctuations refers in this Supplement to the antagonism of adenosine A2A receptors. Several A2A antagonists, including istradefylline and preladenant, have been tested in recent years for this indication, as reviewed in the current Supplement by Pourcher and Huot . The overall global results from the drug‐development programs for these medications have not been as consistent as expected.…”

“…Several A2A antagonists, including istradefylline and preladenant, have been tested in recent years for this indication, as reviewed in the current Supplement by Pourcher and Huot. 19 The overall global results from the drugdevelopment programs for these medications have not been as consistent as expected. For that reason, istradefylline is only marketed for this indication in Japan but not yet in Western countries.…”