N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture.
N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture.
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发表时间：
1987-11
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通讯作者：
M. Goldberg;J. Weiss;P. Pham;D. Choi
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作者：
M. Goldberg;J. Weiss;P. Pham;D. Choi
几种谷氨酸受体拮抗剂减少缺氧皮质神经元损伤的能力在胚胎小鼠细胞培养中进行了定量检测。缺氧8小时的培养次日显示广泛的神经元损伤，添加特异性n -甲基- d -天冬氨酸（NMDA）受体拮抗剂2-氨基-5-磷酸戊酸（APV）可显著减轻这种损伤。APV的保护作用具有浓度依赖性（ED50约为2微米）和立体特异性（D-APV的保护作用约为L-APV的100倍）。神经元保护作用也被观察到与其他几种NMDA拮抗剂：2-氨基-7-磷酸庚酸，苯环利定和(+)-SKF 10047 [(+)- n-烯丙基去甲二嗪]以及非特异性谷氨酸拮抗剂d -谷氨酰甘氨酸和kynurenate。此外，在短暂暴露于高浓度氰化物造成的缺氧神经元损伤的化学模型中，也观察到类似的拮抗剂。相比之下，1mm浓度的谷氨酸二乙基酯和γ -氨基甲基磺酸，这些在一些研究中报道的优先拮抗非nmda谷氨酸受体的化合物，不能保护神经元免受缺氧或氰化物的伤害。这些结果与NMDA受体优先参与缺氧皮质神经元损伤发病机制的假设一致，并表明皮质细胞培养可能是定量表征该损伤药理学的有用系统。
The ability of several glutamate receptor antagonists to reduce hypoxic cortical neuronal injury was quantitatively examined in cell cultures derived from fetal mice. Cultures exposed to hypoxia for 8 hr showed by the following day widespread neuronal injury, which was substantially attenuated by addition of the specific N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (APV). The protective effect of APV was concentration dependent (ED50 about 2 microM) and stereospecific (D-APV approximately 100 times more potent that L-APV). Neuron-protective effects were also observed with several other NMDA antagonists: 2-amino-7-phosphonoheptanoate, phencyclidine and (+)-SKF 10,047 [(+)-N-allylnormetazocine]--as well as with the nonspecific glutamate antagonists D-glutamylglycine and kynurenate. In addition, a similar antagonist profile was observed with a chemical model of hypoxic neuronal injury, produced by brief exposure to high concentrations of cyanide. In contrast, 1 mM concentrations of glutamate diethylester and gamma-aminomethyl sulfonate, compounds reported in some studies to preferentially antagonize non-NMDA glutamate receptors, failed to protect neurons against either hypoxia or cyanide. These results are consistent with the hypothesis that NMDA receptors are preferentially involved in the pathogenesis of hypoxic cortical neuronal injury and suggest that cortical cell culture may be a useful system in which to quantitatively characterize the pharmacology of that injury.