A novel therapeutic strategy to prevent the onset of dyskinesia in models of Parkinson's disease: acute and chronic studies.

Adenosine A2A antagonists have emerged as new class of very promising non dopaminergic drugs in the treatment of Parkinson's Disease (PD). Indeed, the development of new highly selective adenosine A2A antagonists, and their encouraging anti-parkinsonian responses in animal models of PD, has provided a rationale for clinical trials to evaluate the therapeutic potential and the safety of these agents in PD patients [1-3]. Specifically, adenosine A2A antagonists, significantly increase L-dopa efficacy in PD without exacerbating dyskinetic-like behavior [1-3]. The pre-sinaptic serotonin 5-HT1A/1B receptors modulate the release of dopamine formed from L-Dopa in serotoninergic neurons after dopamine denervation [4]. In line with this finding, serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of PD, but at the same time, it reduced L-dopa-induced motility [5]. On this basis, we hypothesize that the early combined administration of preladenant and eltoprazine may produce reduction and prevention of the onset of L-dopa-induced-dyskinesia in a rodent model of PD. Unilateral 6-OHDA-lesioned L-dopa-non primed rats, were treated for 2 weeks with preladenant (0.3 mg/kg) and/or eltoprazine (0.6 mg/kg), alone or in combination with L-dopa (4 mg/kg), and abnormal involuntary movements (AIMs) as index of dyskinesia, were evaluated. Moreover, induction of immediate-early gene zif-268 (an index of long-term changes correlated with dyskinesia) was evaluated [6]. Results show that combined administration of L-dopa plus preladenant plus eltoprazine significantly counteracted and prevented dyskinetic-like behaviors induced by L-dopa, without impairing the efficacy of L-dopa in relieving motor symptoms. Preliminar results showed that zif-268 was increased in striatum of rats treated with L-dopa and L-dopa plus preladenant compared with vehicle. In contrast, rats treated with eltoprazine (with or without preladenant) had lower zif-268 activation after treatment with L-dopa. Results suggest that combination of L-dopa with preladenant and eltoprazine may be a promising therapeutic strategy for treating motor symptoms, delaying, at the same time, the onset of dyskinesia in PD.