Neuroprotective effects of pyruvate following NMDA-mediated excitotoxic insults in hippocampal slices.
Neuroprotective effects of pyruvate following NMDA-mediated excitotoxic insults in hippocampal slices.
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DOI：
10.1016/j.neulet.2010.04.078
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发表时间：
2010-07-12
影响因子：
2.5
通讯作者：
Zorumski CF
中科院分区：
文献类型：
--
作者：
Izumi Y;Zorumski CF
N-甲基-D-天冬氨酸（NMDA）受体的激活和随后的一氧化氮（NO）的释放可能是伴随缺血和其他神经退行性疾病的迟发性神经元损伤的原因。然而，NMDA受体拮抗剂和抑制剂的NO合成，是有限的好处时，兴奋性毒性事件后，这表明确定下游事件，导致神经元变性的重要性。甘油醛-3-磷酸脱氢酶（GAPDH）是一种关键的糖酵解酶，其抑制可能导致糖酵解障碍，是NO的生物学靶点之一，这表明替代性能量底物可能防止神经元损伤。使用大鼠海马脑片从幼年大鼠，我们研究了糖酵解损伤的作用，在NMDA介导的兴奋性毒性和丙酮酸，糖酵解的最终产物，是否防止兴奋性神经元损伤。我们观察到，NMDA的管理急性抑制ATP水平，并导致缓慢发展的抑制GAPDH。与NMDA受体拮抗剂或NO抑制剂不同，当在NMDA受体活化后的时期施用时，外源施用的丙酮酸盐在恢复ATP水平和防止迟发性神经元变性和突触退化方面是有效的。这增加了用维持细胞能量功能的药物治疗可以防止延迟兴奋性毒性的可能性。
The activation of N-methyl-D-aspartate (NMDA) receptors and subsequent release of nitric oxide (NO) are likely contributors to the delayed neuronal damage that accompanies ischemia and other neurodegenerative conditions. NMDA receptor antagonists and inhibitors of NO synthesis, however, are of limited benefit when administered following excitotoxic events, suggesting the importance of determining downstream events that result in neuronal degeneration. Inhibition of glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), a key glycolytic enzyme, which may result in glycolytic impairment, is one of the biological targets of NO. This suggests that alternative energy substrates may prevent neuronal damage. Using rat hippocampal slices from juvenile rats, we examined the role of glycolytic impairment in NMDA mediated excitotoxicity and whether pyruvate, an end product of glycolysis, prevents the excitotoxic neuronal injury. We observed that administration of NMDA acutely depresses ATP levels and result in a slowly developing inhibition of GAPDH. Unlike NMDA receptor antagonists or NO inhibitors, exogenously applied pyruvate is effective in restoring ATP levels and preventing delayed neuronal degeneration and synaptic deterioration when administered in the period following NMDA receptor activation. This raises the possibility that treatment with agents that maintain cellular energy function can prevent delayed excitotoxicity.
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影响因子：
56.9
作者：
SCHURR, A;WEST, CA;RIGOR, BM
通讯作者：
RIGOR, BM
影响因子：
4.7
作者：
Nakamichi, N;Kambe, Y;Yoneda, Y
通讯作者：
Yoneda, Y
影响因子：
4.1
作者：
MARIN, P;MAUS, M;PREMONT, J
通讯作者：
PREMONT, J
影响因子：
6.3
作者：
Zeng, Jianying;Yang, Guo-Yuan;Litt, Lawrence
通讯作者：
Litt, Lawrence
影响因子：
6.1
作者：
Izumi, Y;Izumi, M;Zorumski, CF
通讯作者：
Zorumski, CF