Ammonia neurotoxicity and the mitochondrial permeability transition.
Ammonia neurotoxicity and the mitochondrial permeability transition.
复制标题
氨神经毒性和线粒体通透性转变。
DOI：
10.1023/b:jobb.0000041758.20071.19
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发表时间：
2004
影响因子：
3
通讯作者：
Jayakumar,AR
中科院分区：
文献类型：
--
作者：
Norenberg,MD;RamaRao,KV;Jayakumar,AR
氨是一种主要影响星形胶质细胞的神经毒素。线粒体功能紊乱和氧化应激与线粒体通透性转变（MPT）的诱导有关，似乎与氨神经毒性的机制有关。我们最近发现氨可以诱导培养的星形胶质细胞的MPT。为了阐明MPT的机制，我们研究了氧化应激和氨代谢副产物谷氨酰胺的作用。氨诱导的MPT被抗氧化剂阻断，提示氧化应激的因果作用。谷氨酰胺（4.5 ~ 7.0 mM）直接作用于培养的星形胶质细胞，可增加自由基的产生，诱导MPT。用线粒体谷氨酰胺酶抑制剂6-重氮-5-氧- l -去甲亮氨酸处理星形胶质细胞，完全阻断自由基的形成和MPT，这表明谷氨酰胺水解引起的线粒体高浓度氨可能是谷氨酰胺作用的原因。这些研究表明，氧化应激和谷氨酰胺在诱导与氨神经毒性相关的MPT中起主要作用。
Ammonia is a neurotoxin that predominantly affects astrocytes. Disturbed mitochondrial function and oxidative stress, factors implicated in the induction of the mitochondrial permeability transition (MPT), appear to be involved in the mechanism of ammonia neurotoxicity. We have recently shown that ammonia induces the MPT in cultured astrocytes. To elucidate the mechanisms of the MPT, we examined the role of oxidative stress and glutamine, a byproduct of ammonia metabolism. The ammonia-induced MPT was blocked by antioxidants, suggesting a causal role of oxidative stress. Direct application of glutamine (4.5–7.0 mM) to cultured astrocytes increased free radical production and induced the MPT. Treatment of astrocytes with the mitochondrial glutaminase inhibitor, 6-diazo-5-oxo-L-norleucine, completely blocked free radical formation and the MPT, suggesting that high ammonia concentrations in mitochondria resulting from glutamine hydrolysis may be responsible for the effects of glutamine. These studies suggest that oxidative stress and glutamine play major roles in the induction of the MPT associated with ammonia neurotoxicity.