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首页> 外文OA文献 >Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism
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Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism

机译：选择性mGluR5拮抗剂MPEP和SIB-1893通过反映NMDA受体拮抗作用而降低NMDA或谷氨酸介导的神经元毒性

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The metabotropic glutamate receptors (mGluRs) are a family of G-protein linked receptors that can be divided into three groups (group I, II and III). A number of studies have implicated group I mGluR activation in acute neuronal injury, but until recently it was not possible to pharmacologically differentiate the roles of the two individual subunits (mGluR1 and mGluR5) in this group.We investigated the role of mGluR5 in acute NMDA and glutamate mediated neurodegeneration in cultured rat cortical cells using the mGluR5 antagonists MPEP and SIB-1893, and found that they provide significant protection at concentrations of 20 or 200 μM.These compounds act as effective mGluR5 antagonists in our cell culture system, as indicated by the ability of SIB-1893 to prevent phosphoinositol hydrolysis induced by the specific mGluR5 agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG).However, they also significantly reduce NMDA evoked current recorded from whole cells voltage clamped at −60 mV, and significantly decrease the duration of opening of NMDA channels recorded in the outside out patch configuration.This suggests that although MPEP and SIB-1893 are effective mGluR5 antagonists, they also act as noncompetitive NMDA receptor antagonists. Therefore, the neuroprotective effects of these compounds are most likely mediated through their NMDA receptor antagonist action, and caution should be exercised when drawing conclusions about the roles of mGluR5 based on their use.
机译：代谢型谷氨酸受体（mGluRs）是G蛋白连接的受体家族，可分为三类（I，II和III组）。许多研究表明I组mGluR激活在急性神经元损伤中起作用，但直到最近，尚无法在药理学上区分该组中两个单独的亚基（mGluR1和mGluR5）的作用。我们研究了mGluR5在急性NMDA中的作用。 mGluR5拮抗剂MPEP和SIB-1893在大鼠皮层细胞中介导的谷氨酸介导的神经变性，发现它们在浓度为20或200μM时能提供显着的保护作用。这些化合物在我们的细胞培养系统中可作为有效的mGluR5拮抗剂。 SIB-1893具有预防特定mGluR5激动剂（RS）-2-氯-5-羟基苯基甘氨酸（CHPG）诱导的磷酸肌醇水解的能力，但是，它们也显着降低了固定在-60的全细胞电压下记录的NMDA诱发电流mV，并显着减少了在外出补丁配置中记录的NMDA通道打开的持续时间。这表明尽管MPEP和SI B-1893是有效的mGluR5拮抗剂，它们还充当非竞争性NMDA受体拮抗剂。因此，这些化合物的神经保护作用很可能是通过其NMDA受体拮抗作用来介导的，在根据其用途得出有关mGluR5作用的结论时应谨慎行事。

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