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免疫刺激的小鼠小胶质细胞对N-甲基-D-天冬氨酸介导的神经毒性的增强作用。

Potentiation of N-methyl-D-aspartate-mediated neurotoxicity by immunostimulated murine microglia.

作者信息

Kim W K, Ko K H

机构信息

Department of Pharmacology, College of Medicine, Medical Research Center, Ewha Womans University, Seoul, Republic of Korea.

出版信息

J Neurosci Res. 1998 Oct 1;54(1):17-26. doi: 10.1002/(SICI)1097-4547(19981001)54:1<17::AID-JNR3>3.0.CO;2-K.

Abstract

Microglia have been shown to be immunostimulated by inflammatory cytokines and produce a number of toxic mediators. Here we report that immunostimulated microglia can synergistically enhance the N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity in rat cerebellar granule cells (CGC) in culture. Neurotoxicity was assessed by morphological examination and by measuring the release of lactate dehydrogenase and DNA fragmentation. Cultured microglia were immunostimulated by interferon-gamma (200 U/ml) and lipopolysaccharides (10 microg/ml) and one or two days later they were used for co-culture with CGC. Co-culture of CGC with immunostimulated microglia resulted in a remarkable enhancement of the NMDA receptor-mediated death of CGC. This enhanced neurotoxicity was mimicked by the nitric oxide releaser 3-morpholinosydnonimine (SIN-1) or S-nitroso-N-acetylpenicillamine (SNAP). Superoxide dismutase and catalase, which stabilise NO by removing superoxide anion, ameliorated the potentiation of the NMDA-mediated death of CGC in co-culture with immunostimulated microglia, implying that reactions of NO with superoxide to form peroxynitrite can be implicated in the potentiated neurotoxicity. Our data indicate that immunostimulated microglia, which may involve in various neuropathologies, potentiate the NMDA receptor-mediated excitotoxicity in part through the expression of inducible nitric oxide synthase.

摘要

小胶质细胞已被证明可被炎性细胞因子免疫刺激并产生多种毒性介质。在此我们报告,免疫刺激的小胶质细胞可协同增强培养的大鼠小脑颗粒细胞(CGC)中N-甲基-D-天冬氨酸(NMDA)受体介导的兴奋性毒性。通过形态学检查以及测量乳酸脱氢酶释放和DNA片段化来评估神经毒性。用干扰素-γ(200 U/ml)和脂多糖(10 μg/ml)对培养的小胶质细胞进行免疫刺激,1或2天后将它们用于与CGC共培养。CGC与免疫刺激的小胶质细胞共培养导致NMDA受体介导的CGC死亡显著增强。一氧化氮释放剂3-吗啉代辛二酮(SIN-1)或S-亚硝基-N-乙酰青霉胺(SNAP)可模拟这种增强的神经毒性。超氧化物歧化酶和过氧化氢酶通过去除超氧阴离子来稳定NO,减轻了与免疫刺激的小胶质细胞共培养时NMDA介导的CGC死亡的增强作用,这意味着NO与超氧反应形成过氧亚硝酸盐可能与增强的神经毒性有关。我们的数据表明,可能参与各种神经病理学的免疫刺激的小胶质细胞,部分通过诱导型一氧化氮合酶的表达增强了NMDA受体介导的兴奋性毒性。

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