Chuang D M, Gao X M, Paul S M
Section on Molecular Neurobiology, National Institute of Mental Health, Bethesda, Maryland 20892.
Mol Pharmacol. 1992 Aug;42(2):210-6.
Exposure of cultured cerebellar granule cells to glutamate results in a concentration-dependent (EC50 = 22.7 +/- 0.4 microM) and delayed (24-72 hr) neurotoxicity, which is blocked by the specific N-methyl-D-aspartate (NMDA) receptor antagonists 2-amino-5-phosphovalerate and MK-801 but is unaffected by the non-NMDA receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and 6,7-dinitroquinoxaline-2,3-dione. Although glutamate toxicity in these cells is mediated by the NMDA subtype of glutamate receptor, pretreatment of cerebellar granule cells with subtoxic concentrations of NMDA markedly antagonizes the neurotoxic actions of glutamate, with an IC50 of 55 +/- 4 microM. The neuroprotective effect of NMDA requires a preincubation time of approximately 120 min to be fully manifested and does not require the presence of NMDA during glutamate exposure. These data demonstrate that NMDA receptors mediate both neurotoxicity and neuroprotection in cerebellar granule cells. Among four glutamate receptor agonists tested (NMDA, quisqualate, ibotenate, and kainate), only NMDA was able to provide a robust neuroprotection against glutamate toxicity. Quisqualate was neither neurotoxic nor neuroprotective, whereas ibotenate, which was nontoxic by itself, induced a small degree of neuroprotection. In contrast, kainate, which was neurotoxic to cerebellar granule cells, also provided considerable neuroprotection against glutamate toxicity. Because preincubation of cerebellar granule cells with NMDA fails to alter NMDA receptor-mediated phosphoinositide hydrolysis or the specific binding of [3H]MK-801 to NMDA receptors, it appears that the neuroprotective effects of NMDA are not due to NMDA receptor desensitization.
将培养的小脑颗粒细胞暴露于谷氨酸会导致浓度依赖性（EC50 = 22.7 +/- 0.4 microM）且延迟（24 - 72小时）的神经毒性，这种毒性可被特异性N - 甲基 - D - 天冬氨酸（NMDA）受体拮抗剂2 - 氨基 - 5 - 磷酸缬氨酸和MK - 801阻断，但不受非NMDA受体拮抗剂6 - 氰基 - 7 - 硝基喹喔啉 - 2,3 - 二酮和6,7 - 二硝基喹喔啉 - 2,3 - 二酮的影响。尽管这些细胞中的谷氨酸毒性是由谷氨酸受体的NMDA亚型介导的，但用亚毒性浓度的NMDA预处理小脑颗粒细胞可显著拮抗谷氨酸的神经毒性作用，IC50为55 +/- 4 microM。NMDA的神经保护作用需要约120分钟的预孵育时间才能充分显现，且在谷氨酸暴露期间不需要NMDA的存在。这些数据表明，NMDA受体在小脑颗粒细胞中介导神经毒性和神经保护作用。在所测试的四种谷氨酸受体激动剂（NMDA、quisqualate、ibotenate和kainate）中，只有NMDA能够对谷氨酸毒性提供强大的神经保护作用。quisqualate既无神经毒性也无神经保护作用，而ibotenate本身无毒，可诱导一定程度的神经保护作用。相比之下，对小脑颗粒细胞具有神经毒性的kainate也对谷氨酸毒性提供了相当程度的神经保护作用。由于用NMDA预孵育小脑颗粒细胞不会改变NMDA受体介导的磷酸肌醇水解或[3H]MK - 801与NMDA受体的特异性结合，因此NMDA的神经保护作用似乎不是由于NMDA受体脱敏所致。
