Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and L-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.
Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and L-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.
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DOI：
10.1016/j.neuropharm.2015.02.023
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发表时间：
2015-08
影响因子：
4.7
通讯作者：
Cenci MA
中科院分区：
文献类型：
--
作者：
Iderberg H;Maslava N;Thompson AD;Bubser M;Niswender CM;Hopkins CR;Lindsley CW;Conn PJ;Jones CK;Cenci MA
代谢型谷氨酸受体4(MGlu4)在基底节的“间接途径”中负向调节GABA和谷氨酸的释放，因此被认为是治疗帕金森病运动症状的潜在靶点。在这里，我们广泛地比较了mGlu4阳性变构调节剂(PAM)VU0364770和mGlu4正构体激动剂LSP1-2111在单侧6-OHDA损伤大鼠中产生的行为效应。这些化合物的活性最初是在氟哌啶醇诱导的正常大鼠惊厥测试中评估的，然后在偏侧帕金森病动物模型中评估有效剂量。这两种化合物都不能改善L多巴慢性治疗所引起的运动障碍行为的发展。当与L多巴一起给已建立运动障碍的大鼠时，VU0364770和LSP1-2111都不能改变异常的不自主运动评分。然而，在某些行为测试中，VU0364770增强了低于阈值剂量的L-多巴的运动刺激效应，而LSP1-2111则缺乏这种能力。综上所述，这些结果表明，mGlu4的药理刺激缺乏内在的抗动力障碍活性，但在帕金森病中可能具有DOPA节约活性。对于后一种适应症，mGlu4 PAM似乎比正构体激动剂提供了更好的选择。
Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the ‘indirect pathway’ of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of haloperidol-induced catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a sub-threshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists.
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影响因子：
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