Effects of metabotropic glutamate receptor 5 antagonist MPEP on behaviors and striatal postsynaptic density-95 protein expression in rats with levodopa-induced dyskinesia

Abstract

Objective To investigate the effects of metabotropic glutamate receptor 5 antagonist methyl-6-ethynyl-pyridine (MPEP) on behavior and striatal postsynaptic density-95 (PSD-95) protein expression changes in rats with levodopa-induced dyskinesia (LID). Methods Hemi-parkinsonian rat models were established by stereotaxically injection of 6-hydroxy dopamine (6-OHDA) in the right medial forebrain bundle; then, these 32 Parkinson's disease (PD) rats were randomly divided into four groups (n=8): levodopa (L-DOPA) treatment group, receiving L-DOPA 25 mg/kg+benserazide 6.25 mg/kg; saline group, giving the same volume of saline; MPEP treatment group, receiving 1.5 mg/kg MPEP; and L-DOPA+MPEP treatment group, accepted L-DOPA 25 mg/kg+benserazide 6.25 mg/kg+MPEP 1.5 mg/kg; All rats received intraperitoneal injections twice daily and continued for 21 days. At days 2, 9, 11, 18 and 21, behavior changes of all rats were detected; the protein and mRNA levels of PSD-95 in striatal tissues were detected by Western blotting and real-time PCR, respectively. Results (1) Abnormal involuntary movement scores were significantly decreased in rats of L-DOPA+MPEP treatment group (42.33±12.43, 41.80±13.69 and 40.30±9.76) as compared with those in L-DOPA treatment group (55.56±9.28, 54.89±7.01 and 58.44±7.68) on days 11, 18, and 21 (P<0.05). Forepaw adjusting steps were significantly increased in Parkinson rats of L-DOPA+MPEP treatment group as compared with rats of L-DOPA treatment group (P<0.05); and the increased extent was not decreased as time prolonging. Forepaw adjusting steps were also increased after MPEP treatment alone. Co-administration of L-DOPA with MPEP reversed the shortening of rotational response duration induced by L-DOPA. (2) The up-regulation of PSD-95 protein and mRNA levels in the lesioned striatum was noted in the L-DOPA treatment group (1.39±0.37 and 3.80±1.09), while this trend could be alleviated by coadministration of L-DOPA with MPEP (0.76±0.66 and 1.65±0.81). Conclusion MPEP can alleviate abnormal involuntary movements induced by L-DOPA and strengthen the anti-parkinsonian effect of L-DOPA, which may be related to regulation of striatal PSD-95 expression induced by L-DOPA. Key words: Parkinson's disease; Dyskinesia; Metabotropic glutamate receptor; Postsynaptic density-95