Strasser U, Lobner D, Behrens M M, Canzoniero L M, Choi D W
Department of Neurology, Center for the Study of the Nervous System Injury, Washington University School of Medicine, St Louis, MO 63110, USA.
Eur J Neurosci. 1998 Sep;10(9):2848-55. doi: 10.1111/j.1460-9568.1998.00291.x.
Activation of ion channel-linked glutamate receptors, especially N-methyl-D-aspartate (NMDA) receptors, mediates the excitotoxic effects of glutamate upon central neurons. We examined the hypothesis that activation of group I metabotropic glutamate receptors (mGluRs) would increase NMDA receptor-mediated cortical neuronal death. Addition of the selective group I mGluR agonists, dihydroxyphenylglycine (DHPG) or trans-azetidine-2,4-dicarboxylic acid (t-ADA) potentiated NMDA-induced neuronal death, and application of the group I mGluR-selective antagonist, aminoindan-1,5-dicarboxylic acid (AIDA), as well as the non-selective antagonists methyl-4-carboxyphenylglycine (MCPG) or 4-carboxyphenylglycine (4CPG) reduced NMDA- and kainate-induced neuronal death in murine cortical cultures. The pro-excitotoxic effect of group I mGluR activation may be mediated largely by enhancement of glutamate release, as DHPG potentiated high potassium-stimulated glutamate release, and the protective effects of both AIDA and MCPG were abolished when NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors were blocked immediately after toxic NMDA receptor overstimulation. The present data support the possibility that antagonizing group I mGluRs may be a useful strategy for attenuating excitotoxic neuronal death in certain disease states.
离子通道偶联型谷氨酸受体尤其是N-甲基-D-天冬氨酸（NMDA）受体的激活介导了谷氨酸对中枢神经元的兴奋毒性作用。我们检验了这样一个假说，即I组代谢型谷氨酸受体（mGluRs）的激活会增加NMDA受体介导的皮质神经元死亡。添加选择性I组mGluR激动剂二羟基苯甘氨酸（DHPG）或反式氮杂环丁烷-2,4-二羧酸（t-ADA）可增强NMDA诱导的神经元死亡，而应用I组mGluR选择性拮抗剂氨基茚满-1,5-二羧酸（AIDA）以及非选择性拮抗剂甲基-4-羧基苯甘氨酸（MCPG）或4-羧基苯甘氨酸（4CPG）可减少小鼠皮质培养物中NMDA和海人藻酸诱导的神经元死亡。I组mGluR激活的促兴奋毒性作用可能主要是通过增强谷氨酸释放来介导的，因为DHPG增强了高钾刺激的谷氨酸释放，并且当在毒性NMDA受体过度刺激后立即阻断NMDA和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体时，AIDA和MCPG的保护作用均被消除。目前的数据支持这样一种可能性，即拮抗I组mGluRs可能是在某些疾病状态下减轻兴奋毒性神经元死亡的一种有用策略。
