Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease

Adenosine A(2A) receptors are abundant in the caudate-putamen and involved in the motor control in several species. In MPTP-treated monkeys, A(2A) receptor-blockade with an antagonist alleviates parkinsonian symptoms without provoking dyskinesia, suggesting this receptor may offer a new target for the antisymptomatic therapy of Parkinson's disease. In the present study, a significant neuroprotective effect of A(2A) receptor antagonists is shown in experimental models of Parkinson's disease. Oral administration of A(2A) receptor antagonists protected against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats. A(2A) antagonists also prevented the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice. The neuroprotective property of A(2A) receptor antagonists may be exerted by altering the packaging of these neurotoxins into vesicles, thus reducing their effective intracellular concentration. We therefore conclude that the adenosine A(2A) receptor may provide a novel target for the long-term medication of Parkinson's disease, because blockade of this receptor exerts both acutely antisymptomatic and chronically neuroprotective activities.