A new therapeutic strategy for Parkinson's disease

Preclinical and clinical studies showed that adenosine A2A receptor antagonists, like preladenant, significantly increase L-DOPA efficacy in Parkinson's disease (PD), without exacerbating dyskinetic-like behaviors. Recently, it has been reported that the mixed 5-HT1A/B receptor agonist, eltoprazine, produces a near to full suppression of dyskinetic-like behaviors; however, eltoprazine resulted in a partial reduction of therapeutic effect of L-DOPA. On this basis, we hypothesize that combination of eltoprazine with preladenant may produce suppression of L-DOPA-induced dyskinesia, without impairing the efficacy of L-DOPA in relieving motor symptoms. Thus, unilateral 6-hydroxydopamine-lesioned rats, rendered dyskinetic by repeated treatment with L-DOPA (6mg/kg), were administered with eltoprazine (0.3 or 0.6 mg/kg) and preladenant (0.3 or 1 mg/kg), singularly or in combination with L-DOPA (4 or 6 mg/kg) plus benserazide (6mg/kg), and turning behavior, as index of locomotor activity, and abnormal involuntary movements (AIMs) as index of dyskinesia, were evaluated. Results suggest that combined administration of L-DOPA (4mg/kg) plus eltoprazine (0.6mg/kg) plus preladenant (0.3mg/kg) significantly reduced dyskinetic-like behaviors, as revealed by AIMs- test without impairing the motor activity, as revealed by similar number of contralateral and ipsilateral turns, evaluated with turning test. Overall these data suggest the use of the combination of L-DOPA (4mg/kg) with eltoprazine (0.6mg/kg) and preladenant (0.3mg/kg) as new therapeutic strategy for treating motor symptoms and dyskinesia in PD. Ongoing experiments are meant to evaluate whether the positive effect of this drug combination can be maintained over a chronic administration