Antidyskinetic Treatment with the mGluR5 Antagonist MPEP Affects CaMKII/CREB/BDNF Molecular Pathways in the Parkinsonian Striatum

Abstract

Background L-DOPA is still the gold-standard drug for the treatment of Parkinson's disease (PD). However, the long-term therapy often causes L-DOPA-induced dyskinesia (LID). Metabotropic glutamate receptor type 5 (mGluR5) is abundant in the basal ganglia, and its antagonists is thought to alleviates LID, but the underlying mechanisms have remained unclear. Methods We used 6-hydroxydopamine-lesioned rats to create PD rat model, PD rats were daily treated with L-DOPA alone or with MPEP 30 min before L-DOPA for 3 weeks, and at least 21 days of L-DOPA was administrated followed with microinjection of saline, CaMKII antagonist KN-93, anti-CREB, or anti-BDNF into the lesioned striatum of all the PD rats. The behavioral evaluation of abnormal involuntary movements(AIM) and rotational behavior tests were performed on the 2, 9, 11, 18, 21 and 23 days after drug application, and to tested the protein level of mGluR5, CaMKII, CREB and BDNF by western blot. Results Our results showed that MPEP cotreatment attenuates the abnormal involuntary movements, reversed the reduction of rotational response duration, and reduced overexpression of striatal mGluR5 and CaMKII/CREB/BDNF in the LID rats. Furthermore, we found that the CaMKII inhibitor KN-93, anti-CREB and anti-BDNF intrastriatal injection partly attenuates LID; KN-93 downregulated the striatal p-CaMKII, p-CREB and BDNF expression of the lesioned side, but the striatal mGluR5 expression without inhibition; anti-CREB downregulated the striatal p-CREB and BDNF expression of the lesioned side, but the striatal mGluR5 and p-CaMKII expression without inhibition; anti-BDNF downregulated the striatal BDNF expression of the lesioned side, but the mGluR5, CaMKII and CREB protein without inhibition. Conclusions These fundings suggested that mGluR5 specific antagonist MPEP attenuates L-DOPA-induced dyskinesia through affects CaMKII/CREB/BDNF molecular pathways in the striatum in this LID rat model.