Symptomatic and Neuroprotective Effects of A2A Receptor Antagonists in Parkinson’s Disease

The motor symptoms of Parkinson’s disease (PD) are due primarily to the degeneration of the dopaminergic nigrostriatal pathway; however other neurotransmitters besides dopamine are affected in the disease. Treatment of PD is largely unsatisfactory due to several side effects such as “on/off,” “wearing-off,” and dyskinesia, associated with dopaminergic chronic therapy. Therefore, new pharmacological approaches based on non-dopaminergic therapy have been recently called for a broadening of therapeutic options beyond traditional dopaminergic drugs. Adenosine A2A receptors have a selective localization in richly dopamine-innervated areas and A2A receptor antagonists can modulate GABA and glutamate release in basal ganglia offering a unique opportunity to modulate basal ganglia functions mediated by dopamine. Indeed, A2A receptor antagonists have been shown to restore motor function and contrast parkinsonian tremor acutely, either alone or in combination with dopaminergic drugs, in experimental models of PD. Moreover, in clinical trials, adenosine A2A receptor antagonists reduce “off” time in patients with PD receiving optimal dopaminergic therapy without the exacerbation of dyskinesia. In addition preclinical data have shown that adenosine A2A receptor antagonists help to prevent neurodegeneration in PD, raising the possibility of their use as disease-modifying agents. With their proposed symptomatic and neuroprotective efficacy, A2A receptor antagonists might be realistic prospects to advance PD therapeutics.