Monje M L, Chatten-Brown J, Hye S E, Raley-Susman K M
Department of Biology, Vassar College, Box 189, Poughkeepsie, NY 12604-0189, USA.
Brain Res. 2000 Feb 28;857(1-2):172-82. doi: 10.1016/s0006-8993(99)02404-x.
Neuronal protein synthesis is inhibited in CA1 pyramidal neurons for many hours after ischemia, hypoxia or hypoglycemia. This inhibition precedes cell death, is a hallmark characteristic of necrotic damage and may play a key role in the death of vulnerable neurons after these insults. The sequence of events leading to this inhibition remains to be fully elucidated. The protein synthesis failure after 7.5 min anoxia/aglycemia in the rat hippocampal slice can be prevented by blocking N-methyl-D-aspartate receptors in a reduced calcium environment during the insult. In this study, we demonstrate that N-methyl-D-aspartate exposure directly causes a dose-dependent, receptor-mediated and prolonged protein synthesis inhibition in CA1 pyramidal neurons. The free radical scavenger Vitamin E significantly attenuates this damage due to low concentrations of N-methyl-D-aspartate (10 microM). Free radical generation by xanthine/xanthine oxidase (XOD) can directly damage protein synthesis in neurons of the slice. Vitamin E, ascorbic acid and N-acetylcysteine can each prevent the damage due to anoxia/aglycemia and to higher concentrations of N-methyl-D-aspartate (50 microM), provided calcium levels are reduced concomitantly. These findings indicate that both free radicals and calcium play a role in the sequence of events leading to protein synthesis failure after energetic stress like anoxia/aglycemia. They further suggest that the mechanism by which N-methyl-D-aspartate receptor activation damages protein synthesis involves free radical generation.
在缺血、缺氧或低血糖后，CA1锥体神经元中的神经元蛋白质合成会被抑制数小时。这种抑制在细胞死亡之前发生，是坏死性损伤的一个标志性特征，并且可能在这些损伤后易损神经元的死亡中起关键作用。导致这种抑制的事件顺序仍有待充分阐明。在损伤期间，通过在低钙环境中阻断N-甲基-D-天冬氨酸受体，可以预防大鼠海马切片在缺氧/无糖血症7.5分钟后的蛋白质合成失败。在本研究中，我们证明N-甲基-D-天冬氨酸的暴露直接导致CA1锥体神经元中剂量依赖性、受体介导的和长时间的蛋白质合成抑制。自由基清除剂维生素E可显著减轻低浓度N-甲基-D-天冬氨酸（10微摩尔）所致的这种损伤。黄嘌呤/黄嘌呤氧化酶（XOD）产生的自由基可直接损害切片神经元中的蛋白质合成。如果同时降低钙水平，维生素E、抗坏血酸和N-乙酰半胱氨酸均可预防缺氧/无糖血症以及较高浓度N-甲基-D-天冬氨酸（50微摩尔）所致的损伤。这些发现表明，自由基和钙在导致缺氧/无糖血症等能量应激后蛋白质合成失败的事件顺序中均起作用。它们进一步表明，N-甲基-D-天冬氨酸受体激活损害蛋白质合成的机制涉及自由基的产生。
