Adenosine A2A receptor antagonists in the therapy of Parkinson's disease

The search of therapies alternative to L-DOPA or dopamine receptor agonists for the treatment of Parkinson’s disease (PD) is very active and the adenosine A2A receptor, for his interaction with the dopamine D2 receptor have became particularly attractive. Recent evidences obtained in rodent and primate models of PD and preliminary clinical trials, indicate that adenosine A2A receptor antagonists might represent a new valuable therapeutic tool for the treatment of PD. In this study we have evaluated the effect of different A2A receptor antagonists in the unilateral 6-hydroxydopamine (6- OHDA) rat model of PD and in the tacrine model of parkinsonian tremor. In 6-OHDA lesioned rats, acute administration of A2A receptor antagonists counteracted the impairments in the initiation of stepping movements, in the adjusting step and in the vibrissaeevoked forelimb placing induced by the lesion and increased the turning behavior induced by L-DOPA. Furthermore, in the tacrine model of parkinsonian tremor A2A receptor antagonists counteracted tacrine-induced bursts of tremulous jaw movements. In chronic studies, A2A receptor antagonistsþL-DOPA in contrast to L-DOPA alone, did not induce sensitisation in turning behavior and induced a lower incidence of abnormal involuntary movements, two tests which evaluate dyskinetic side effects. The results indicate that A2A receptor antagonists may be beneficial in motor impairment and tremor which characterize PD. Furthermore chronic studies suggest that that A2A receptor antagonists might not produce detrimental long-term responses associated to dyskinetic-like side effects.