Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis
Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis
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DOI：
10.1002/jnr.10107
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发表时间：
2002-01-01
影响因子：
4.2
通讯作者：
Barbeito, L
中科院分区：
文献类型：
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作者：
Cassina, P;Peluffo, H;Barbeito, L
由一氧化氮（NO）及其毒性代谢产物过氧亚硝酸盐介导的氧化应激先前已与肌萎缩侧索硬化症（ALS）中的运动神经元变性相关。在家族性和散发性ALS中，退化的脊髓运动神经元通常被表达诱导型NO合酶（NOS）的反应性星形胶质细胞所包围，这表明星形胶质细胞可能在ALS中起致病作用。我们在这里报告说，短暂暴露的脊髓星形胶质细胞单层过氧亚硝酸盐（0.25-1毫米）引起持久的反应性形态变化的特点是过程轴承细胞显示强烈的胶质细胞酸性蛋白和NOS免疫反应。此外，过氧亚硝酸盐引起星形胶质细胞促进随后铺在单层上的胚胎运动神经元的凋亡。接种后24小时内发生神经元死亡，如活化的半胱天冬酶-3和硝基酪氨酸阳性染色的退化运动神经元的存在所证明的。运动神经元的死亡在很大程度上防止NOS抑制剂和过氧亚硝酸清除剂，但不是营养因子，否则将支持运动神经元的生存星形胶质细胞的情况下。细菌脂多糖，一个众所周知的炎症刺激，诱导NOS在星形胶质细胞中的表达，引发了相同的影响星形胶质细胞过氧亚硝酸盐。因此，脊髓星形胶质细胞响应细胞外过氧亚硝酸盐通过采用一种表型，这是细胞毒性运动神经元通过过氧亚硝酸盐依赖的机制。(C)2002 Wiley-Liss，Inc.
Oxidative stress mediated by nitric oxide (NO) and its toxic metabolite peroxynitrite has previously been associated with motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Degenerating spinal motor neurons in familial and sporadic ALS are typically surrounded by reactive astrocytes expressing the inducible form of NO synthase (NOS), suggesting that astroglia may have a pathogenic role in ALS. We report here that a brief exposure of spinal cord astrocyte monolayers to peroxynitrite (0.25-1 mM) provoked long-lasting reactive morphological changes characterized by process-bearing cells displaying intense glial fibrillary acidic protein and NOS immunoreactivity. Furthermore, peroxynitrite caused astrocytes to promote apoptosis of embryonic motor neurons subsequently plated on the monolayers. Neuronal death occurred within 24 hr after plating, as evidenced by the presence of degenerating motor neurons positively stained for activated caspase-3 and nitrotyrosine. Motor neuron death was largely prevented by NOS inhibitors and peroxynitrite scavengers but not by trophic factors that otherwise will support motor neuron survival in the absence of astrocytes. The bacterial lipopolysaccharide, a well-known inflammatory stimulus that induces NOS expression in astrocytes, provoked the same effects on astrocytes as peroxynitrite. Thus, spinal cord astrocytes respond to extracellular peroxynitrite by adopting a phenotype that is cytotoxic to motor neurons through peroxynitrite-dependent mechanisms. (C) 2002 Wiley-Liss, Inc.