Levodopa (L-DOPA) is still the most effective drug for the treatment of Parkinson's disease (PD). However, the long-term therapy often triggers L-DOPA-induced dyskinesia (LID). Metabotropic glutamate receptor type 5 (mGluR5) is abundant in the basal ganglia, and its inhibition is thought to modulate postsynaptic excitatory synaptic transmission and glutamate hyperactivity in PD and LID. In this report, we examined the effects of mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on LID and synaptic components in the PD model rat. We found the selective mGluR5 antagonist MPEP attenuated abnormal involuntary movements, prolonged the duration of rotational response, reversed the decrease of left forepaw adjusting steps, and reduced overexpression of striatal mGluR5 in the LID rats. Moreover, our results showed much thicker postsynaptic densities, narrower synapse cleft, as well as the increased ratio of perforated synapses induced by L-DOPA treatment, while coadministration of L-DOPA and MPEP reversed these postsynaptic effects. Finally, MPEP reduced overexpression of the two postsynaptic proteins (PSD-95 and SAP102) induced by L-DOPA treatment. Hence, these results provide evidence that aberrant neural plasticity at corticostriatal synapses in the striatum is closely correlated with the occurrence of LID, and targeted inhibition of mGluR5 by MPEP alleviates LID in the PD rat model.

中文翻译：

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m-GluR5拮抗剂MPEP在6-OHDA损伤的大鼠中改善了L-DOPA引起的运动障碍和皮质口突触组件的过表达。

左旋多巴（L-DOPA）仍然是治疗帕金森氏病（PD）的最有效药物。但是，长期治疗通常会引发L-DOPA诱发的运动障碍（LID）。代谢型谷氨酸受体5型（mGluR5）在基底神经节中丰富，其抑制作用被认为可调节PD和LID中的突触后兴奋性突触传递和谷氨酸过动。在此报告中，我们研究了mGluR5特异性拮抗剂2-甲基-6-（苯基乙炔基）吡啶（MPEP）对PD模型大鼠的LID和突触成分的影响。我们发现选择性mGluR5拮抗剂MPEP可减轻LID大鼠的异常不自主运动，延长旋转反应的持续时间，逆转左前臂调节步骤的减少，并减少纹状体mGluR5的过表达。此外，我们的结果显示，L-DOPA治疗可诱导突触后密度更大，突触裂隙更窄以及穿孔突触的比例增加，而L-DOPA和MPEP并用可逆转这些突触后作用。最后，MPEP减少了L-DOPA处理诱导的两种突触后蛋白（PSD-95和SAP102）的过表达。因此，这些结果提供了证据，纹状体的皮质口突触处的异常神经可塑性与LID的发生密切相关，MPEP靶向抑制mGluR5可以减轻PD大鼠模型中的LID。MPEP减少了L-DOPA处理诱导的两种突触后蛋白（PSD-95和SAP102）的过表达。因此，这些结果提供了证据，纹状体的皮质口突触处的异常神经可塑性与LID的发生密切相关，MPEP靶向抑制mGluR5可以减轻PD大鼠模型中的LID。MPEP减少了L-DOPA处理诱导的两种突触后蛋白（PSD-95和SAP102）的过表达。因此，这些结果提供了证据，纹状体的皮质口突触处的异常神经可塑性与LID的发生密切相关，MPEP靶向抑制mGluR5可以减轻PD大鼠模型中的LID。