Oleoylethanolamide reduces L-DOPA-induced dyskinesia via TRPV1 receptor in a mouse model of Parkinson´s disease

Abstract

The long-term use of levodopa (L-DOPA) in Parkinson's disease (PD) results in the development of abnormal involuntary movements called L-DOPA-induced dyskinesias. Increasing evidences suggest that the endocannabinoid system may play a role in the modulation of dyskinesias. In this work, we assessed the antidyskinetic effect of the endocannabinoid analog oleoylethanolamide (OEA), an agonist of PPARα and antagonist of TRPV1 receptors. We used a hemiparkinsonian model of PD in mice with 6-OHDA striatal lesion. The chronic L-DOPA treatment developed intense axial, forelimb and orolingual dyskinetic symptoms, as well as contralateral rotations. Treatment with OEA reduced all these symptoms without reducing motor activity or the therapeutic motor effects of L-DOPA. Moreover, the OEA-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of dyskinesia. OEA reduced FosB striatal overexpression and phosphoacetylation of histone 3, both molecular markers of L-DOPA-induced dyskinesias. We found that OEA antidyskinetic properties were mediated by TRPV1 receptor, as pretreatment with capsaicin, a TRPV1 agonist, blocked OEA antidyskinetic actions, as well as the reduction in FosB- and pAcH3-overexpression induced by L-DOPA. This study supports the hypothesis that the endocannabinoid system plays an important role in the development and expression of dyskinesias and might be an effective target for the treatment of L-DOPA-induced dyskinesias. Importantly, there was no development of tolerance to OEA in any of the parameters we examined, which has important implications for the therapeutic potential of drugs targeting the endocannabinoid system.