APOPTOSIS AND NECROSIS - 2 DISTINCT EVENTS INDUCED, RESPECTIVELY, BY MILD AND INTENSE INSULTS WITH N-METHYL-D-ASPARTATE OR NITRIC-OXIDE SUPEROXIDE IN CORTICAL CELL-CULTURES
APOPTOSIS AND NECROSIS - 2 DISTINCT EVENTS INDUCED, RESPECTIVELY, BY MILD AND INTENSE INSULTS WITH N-METHYL-D-ASPARTATE OR NITRIC-OXIDE SUPEROXIDE IN CORTICAL CELL-CULTURES
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DOI：
10.1073/pnas.92.16.7162
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发表时间：
1995-08-01
影响因子：
11.1
通讯作者：
LIPTON, SA
中科院分区：
文献类型：
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作者：
BONFOCO, E;KRAINC, D;LIPTON, SA
n -甲基- d -天冬氨酸（NMDA）受体介导的神经毒性可能部分依赖于一氧化氮（NO）和超氧阴离子（O-2）的产生。-))，反应生成过氧亚硝酸盐（OONO-）。这种形式的神经毒性被认为是多种急性和慢性神经系统疾病（包括局灶性缺血、创伤、癫痫、亨廷顿病、阿尔茨海默病、肌萎缩侧索硬化症、艾滋病痴呆和其他神经退行性疾病）损伤的最终共同途径。在这里，我们报道皮质神经元暴露于相对较短时间或低浓度的NMDA、s -亚硝基半胱氨酸或3- morpholinosydnon亚胺（产生低水平的过氧亚硝酸盐），诱导以凋亡特征为主的延迟形式的神经毒性。超氧化物歧化酶和过氧化氢酶预处理去除O-2。-)部分阻止s -亚硝基半胱氨酸或3- morpholinosydnon亚胺引发的细胞凋亡过程。相反，高浓度的NMDA或过氧亚硝酸盐会导致坏死细胞损伤，表现为急性肿胀和溶解，而超氧化物歧化酶和过氧化氢酶无法改善这种损伤。因此，根据初始损伤的强度，NMDA或一氧化氮/超氧化物可导致神经元细胞凋亡或坏死损伤。
N-Methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity may depend, in part, on the generation of nitric oxide (NO.) and superoxide anion (O-2(.-)), which react to form peroxynitrite (OONO-). This form of neurotoxicity is thought to contribute to a final common pathway of injury in a wide variety of acute and chronic neurologic disorders, including focal ischemia, trauma, epilepsy, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, AIDS dementia, and other neurodegenerative diseases. Here, we report that exposure of cortical neurons to relatively short durations or low concentrations of NMDA, S-nitrosocysteine, or 3-morpholinosydnonimine, which generate low levels of peroxynitrite, induces a delayed form of neurotoxicity predominated by apoptotic features. Pretreatment with superoxide dismutase and catalase to scavenge O-2(.-) partially prevents the apoptotic process triggered by S-nitrosocysteine or 3-morpholinosydnonimine. In contrast, intense exposure to high concentrations of NMDA or peroxynitrite induces necrotic cell damage characterized by acute swelling and lysis, which cannot be ameliorated by superoxide dismutase and catalase. Thus, depending on the intensity of the initial insult, NMDA or nitric oxide/superoxide can result in either apoptotic or necrotic neuronal cell damage.