Neuroprotective effect of L-DOPA co-administered with the adenosine A 2A 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 A 2A 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 tyrosine-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.