Endogenous D-serine is involved in induction of neuronal death by N-methyl-D-aspartate and simulated ischemia in rat cerebrocortical slices
Endogenous D-serine is involved in induction of neuronal death by N-methyl-D-aspartate and simulated ischemia in rat cerebrocortical slices
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DOI：
10.1124/jpet.104.070912
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发表时间：
2004-11-01
影响因子：
3.5
通讯作者：
Akaike, A
中科院分区：
文献类型：
--
作者：
Katsuki, H;Nonaka, M;Akaike, A
新出现的证据表明，D-丝氨酸，而不是甘氨酸作为一种内源性激动剂在甘氨酸位点的N-甲基-D-天冬氨酸（NMDA）亚型的谷氨酸受体，在几个神经组织，包括发育中的小脑和视网膜。在这里，我们研究了内源性D-丝氨酸是否在大脑皮层兴奋性毒性损伤引起的神经元损伤中起着重要作用，使用大鼠脑切片保持在一个定义的盐溶液。竞争性甘氨酸位点拮抗剂2，7-dichlorokynurenic acid可明显抑制NMDA或氧-糖剥夺（模拟缺血）诱导的神经元细胞死亡。甘氨酸或D-丝氨酸的添加不增加NMDA或模拟缺血引起的神经元损伤，表明在切片内内源性提供了足够量的甘氨酸位点激动剂。应用D-氨基酸氧化酶（一种降解D-丝氨酸的酶）可显著抑制NMDA和模拟缺血引起的神经元损伤，并可通过加入过量的D-丝氨酸或甘氨酸逆转。对NMDA或缺血诱导损伤的甘氨酸位点拮抗剂的敏感性不受非NMDA受体拮抗剂的存在的影响，这表明原代培养的星形胶质细胞中所证明的红藻氨酸受体刺激的D-丝氨酸释放对神经元损伤的程度没有显着贡献在这些环境中。本研究结果表明，内源性供应的D-丝氨酸作为一个甘氨酸位点激动剂是重要的神经元损伤涉及NMDA受体过度激活在大脑皮层。
Emerging evidence indicates that D-serine rather than glycine serves as an endogenous agonist at glycine site of the N-methyl-D- aspartate ( NMDA) subtype of glutamate receptors, in several nervous tissues, including the developing cerebellum and the retina. Here, we examined whether endogenous D-serine plays a significant role in neuronal damage resulting from excitotoxic insults in the cerebral cortex, using rat brain slices maintained in a defined salt solution. Neuronal cell death induced by application of NMDA or by oxygen-glucose deprivation ( simulated ischemia) was markedly suppressed by a competitive glycine site antagonist 2,7-dichlorokynurenic acid. Addition of glycine or D-serine did not augment neuronal damage by NMDA or simulated ischemia, indicating that sufficient amount of glycine site agonist(s) is supplied endogenously within the slices. Application of D-amino acid oxidase, an enzyme that degrades D-serine, markedly inhibited neuronal damage by NMDA and simulated ischemia, which was reversed by addition of excess D-serine or glycine. Sensitivity to the glycine site antagonist of NMDA- or ischemia-induced damage was not affected by the presence of a non-NMDA receptor antagonist, suggesting that kainate receptor-stimulated D-serine release as demonstrated in primary cultured astrocytes does not contribute significantly to the extent of neuronal injury in these settings. The present results suggest that endogenous supply of D-serine as a glycine site agonist is important for neuronal injury involving NMDA receptor overactivation in the cerebral cortex.