Experimental Studies Of Metabotropic Glutamate Receptor 5 Antagonist, MPEP, On L-DOPA-induced Dyskinesia Rats With Parkinson’s Disease

Part I Study of metabotropic glutamate receptor 5 antagonist, MPEP, on thebehavior of L-DOPA-induced dyskinesia rats with Parkinson’s diseaseObjective: To establish the rat model of Parkinson’s disease(PD) and levodopa-induced dyskinesia(LID) and investigate the effect of metabotropic glutamate receptor 5(m Glu R5) antagonist, MPEP, on the behavior of PD and LID rats.Methods: Hemiparkinsonian rat model was established by stereotaxically injection of 6-OHDA in the right medial forebrain bundle. Successfully PD rats were randomly divided into four groups(n=12): saline group, L-DOPA group, MPEP gooup, MPEP plus L-DOPA group. All rats received intraperitoneal injections of saline or the drugs twice daily and continued for 21 days. At days 2, 9, 11, 18 and 21, behavior changes, including abnormal involuntary movement(AIM), contralateral forepaw adjusting steps and rotational response duration of all rats were performed.Results: 1. MPEP plus L-DOPA treatment significantly decreased axial AIM score at day 21(P<0.05). Moreover, the limb AIM scores on the days of 11, 18 and 21 an total AIM score at day 21 in MPEP plus L-DOPA group were also diminished(P<0.05). 2. Contralateral forepaw adjusting steps were significantly increased after treated by L-DOPA during the whole treatment(P<0.05), but the increasing extent has a tendency to decrease as time prolong. MPEP plus L-DOPA treatment also significantly increased contralateral forepaw adjusting steps(P<0.05) and the increasing extent was not decreased as time prolong. MPEP treatment alone also increased the contralateral forepaw adjusting steps at days 9, 11, 18 and 21(P<0.05). 3. The rats treated with L-DOPA alone developed a time-dependent reduction in L-DOPA induced rotational response duration(P<0.05). By contrast, the L-DOPA induced rotational response duration almost remained unchanged throughout the 21 days observation period in MPEP plus L-DOPA rats. Moreover, at day 21, the rotational response duration in MPEP plus L-DOPA group was longer than that in L-DOPA group(P<0.05).Conclusion: 1.MPEP could alleviate the development of LID. 2. MPEP could enhance the antiparkinsonian effect of L-DOPA. 3. MPEP has the effect to improve the motor symptom of PD. Part II Study of metabotropic glutamate receptor 5 antagonist, MPEP, on theeffects of dorsal striatum synaptic ultrastructure and the related proteinsexpression of L-DOPA-induced dyskinesia rats with Parkinson’s diseaseObjective: To investingate the effects of m Glu R5 antagonist, MPEP, on the striatal m Glu R5 and postsynaptic density-95(PSD-95) protein expression and dorsal striatum synaptic ultrastructural changes in rats with LID.Methods: Successfully PD rats continually received injection of saline, L-DOPA, MPEP, MPEP plus L-DOPA respectively for 21 days. All rats were sacrificed after the last injection. Dorsal striatum was extracted for the observation of synaptic ultrastructure. Striatum was also extracted and western blot was used for the detection of m Glu R5 and PSD-95, real-time PCR was used to detecte PSD-95 m RNA level.Results: 1. Compared with rats treated by saline, rats treated by L-DOPA have a thicker postsynaptic density, a narrower synaptic cleft and a higher ratio of perforated synapse(P<0.05). But MPEP plus L-DOPA treatment could alleviated these changes(P<0.05). 2. L-DOPA treatment increased the protein expression of m Glu R5 and PSD-95 in the lesioned striatum(P<0.05), but co-treated with MPEP could reversed these changes(P<0.05). 3. L-DOPA treatment increased the m RNA level of PSD-95 in the lesioned striatum(P<0.05), but co-application of MPEP attenuated this change(P<0.05).Conclusion: 1. m Glu R5 antagonist, MPEP, could attenuate dorsal striatum synaptic ultrastucture abnormal changes induced by L-DOPA. 2. m Glu R5 and PSD-95 participate in the pathogenesis of LID. 3. MPEP could reverse abnormal expression of striatal m Glu R5 and PSD-95 induced by L-DOPA.