Neuroprotective effect of L-DOPA co-administered with the adenosine A2A receptor agonist CGS 21680 in an animal model of Parkinson's disease

Adenosine A(2A) receptors are a new target for drug development in Parkinson's disease. Some experimental and clinical data suggest that A(2A) receptor antagonists can provide symptomatic improvement by potentiating the effects of (L)-DOPA as well as a decrease in secondary effects such as (L)-DOPA-induced dyskinesia. (L)-DOPA-induced behavioral sensitization in unilateral 6-hydroxydopamine-lesioned rats is frequently used as an experimental model of (L)-DOPA-induced dyskinesia. In the present work this model was used to evaluate the effect of the A(2A) receptor agonist CGS 21680 and the AA receptor antagonist MSX-3 on (L)-DOPA-induced behavioral sensitization and 6-hydroxydopamine-induced striatal dopamine denervation. (L)-DOPA-induced behavioral sensitization was determined as an increase in (L)-DOPA-induced abnormal involuntary movements and enhancement of apomorphine-induced turning behavior. Striatal dopamine innervation was determined by measuring tyro sine-hydroxylase immunoreactivity. Chronic administration of MSX-3 was not found to be effective at counteracting (L)-DOPA-induced behavioral sensitization. On the other hand, CGS 21680 completely avoided the development of (L)-DOPA-induced behavioral sensitization. The analysis of the striatal dopamine innervation showed that (L)-DOPA-CGS 21680 co-treatment conferred neuroprotection to the toxic effects of 6-hydroxydopamine. This neuroprotective effect was dependent on A(2A) and D-2 receptor stimulation, since it was counteracted by MSX-3 and by the D-2 receptor antagonist haloperidol. These results open new therapeutic avenues in early events in Parkinson's disease. (C) 2004 Elsevier Inc. All rights reserved.