Dekundy Andrzej, Pietraszek Malgorzata, Schaefer Daniela, Cenci M Angela, Danysz Wojciech
Preclinical R&D, Merz Pharmaceuticals GmbH, Eckenheimer Landstr. 100, 60318 Frankfurt am Main, Germany.
Brain Res Bull. 2006 Apr 14;69(3):318-26. doi: 10.1016/j.brainresbull.2005.12.009. Epub 2006 Jan 25.
The present study was devoted to investigate the effects of the metabotropic glutamate receptor(mGluR)5 antagonist [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and the mGluR1 antagonist, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM), in animal studies indicative of antiparkinsonian-like activity such as haloperidol-induced catalepsy, hypoactivity in open field following haloperidol, and rotation in rats with unilateral 6-hydroxydopamine(OHDA)-induced lesions of the midbrain dopaminergic system (alone and in combination with L-DOPA). Moreover, antidyskinetic activity of different mGluR ligands was evaluated in the rat model of L-DOPA-induced dyskinesia. Both MTEP (5 mg/kg) and EMQMCM (4 mg/kg) slightly inhibited haloperidol (0.5 mg/kg)-induced catalepsy. However, neither substance reversed the hypoactivity produced by haloperidol (0.2 mg/kg). Although MTEP did not produce significant turning, it inhibited contralateral rotations after L-DOPA (at 5 mg/kg) and alleviated L-DOPA-induced dyskinesia (at 2.5 and 5 mg/kg) in 6-OHDA-lesioned rats. In contrast, mGluR1 antagonists EMQMCM and RS-1-aminoindan-1,5-dicarboxylic acid (AIDA) failed to modify L-DOPA-induced dyskinesia. The results of the present study suggest that either subtype of group I of mGluRs may be involved in the pathologically altered circuitry in the basal ganglia. However, the equivocal results do not strongly support the hypothesis that mGluR1 and mGluR5 antagonists may be beneficial in the symptomatic treatment of Parkinson's disease. However, mGluR5 antagonists may prove useful for the symptomatic treatment of L-DOPA-induced dyskinesia.
本研究致力于在动物实验中研究代谢型谷氨酸受体（mGluR）5拮抗剂[（2-甲基-1,3-噻唑-4-基）乙炔基]吡啶（MTEP）和mGluR1拮抗剂（3-乙基-2-甲基喹啉-6-基）-（4-甲氧基环己基）-甲酮甲磺酸盐（EMQMCM）的抗帕金森样活性，这些实验包括氟哌啶醇诱导的僵住症、氟哌啶醇给药后在旷场中的活动减少以及单侧6-羟基多巴胺（OHDA）诱导的中脑多巴胺能系统损伤大鼠的旋转行为（单独及与左旋多巴联合使用）。此外，在左旋多巴诱导的异动症大鼠模型中评估了不同mGluR配体的抗异动症活性。MTEP（5毫克/千克）和EMQMCM（4毫克/千克）均轻微抑制了氟哌啶醇（0.5毫克/千克）诱导的僵住症。然而，两种物质均未逆转氟哌啶醇（0.2毫克/千克）引起的活动减少。虽然MTEP未产生明显的旋转，但它抑制了左旋多巴（5毫克/千克）给药后的对侧旋转，并减轻了6-OHDA损伤大鼠中左旋多巴诱导的异动症（剂量为2.5和5毫克/千克）。相比之下，mGluR1拮抗剂EMQMCM和RS-1-氨基茚满-1,5-二羧酸（AIDA）未能改变左旋多巴诱导的异动症。本研究结果表明，I组mGluR的任一亚型可能参与了基底神经节中发生病理改变的神经回路。然而，这些模棱两可的结果并不有力支持mGluR1和mGluR5拮抗剂可能对帕金森病的症状治疗有益的假说。不过，mGluR5拮抗剂可能被证明对左旋多巴诱导的异动症的症状治疗有用。
