This study investigated the role of cellular antioxidant defense mechanisms in modulating the neurotoxicity of domoic acid (DomA), by using cerebellar granule neurons (CGNs) from mice lacking the modifier subunit of glutamate-cysteine ligase (Gclm). Glutamate-cysteine ligase (Glc) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis. CGNs from Gclm (-/-) mice have very low levels of GSH and are 10-fold more sensitive to DomA-induced toxicity than CGNs from Gclm (+/+) mice. GSH ethyl ester decreased, whereas the Gcl inhibitor buthionine sulfoximine increased DomA toxicity. Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors and of N-methyl-D-aspartate (NMDA) receptors blocked DomA toxicity, and NMDA receptors were activated by DomA-induced l-glutamate release. The differential susceptibility of CGNs to DomA toxicity was not due to a differential expression of ionotropic glutamate receptors, as evidenced by similar calcium responses and L-glutamate release in the two genotypes. A calcium chelator and several antioxidants antagonized DomA-induced toxicity. DomA caused a rapid decrease in cellular GSH, which preceded toxicity, and the decrease was primarily due to DomA-induced GSH efflux. DomA also caused an increase in oxidative stress as indicated by increases in reactive oxygen species and lipid peroxidation, which was subsequent to GSH efflux. Astrocytes from both genotypes were resistant to DomA toxicity and presented a diminished calcium response to DomA and a lack of DomA-induced L-glutamate release. Because polymorphisms in the GCLM gene in humans are associated with low GSH levels, such individuals, as well as others with genetic conditions or environmental exposures that lead to GSH deficiency, may be more susceptible to DomA-induced neurotoxicity.

译文

这项研究通过使用缺乏谷氨酸-半胱氨酸连接酶修饰亚基 (Gclm) 的小鼠的小脑颗粒神经元 (CGNs),研究了细胞抗氧化防御机制在调节软骨藻酸 (DomA) 神经毒性中的作用。谷氨酸-半胱氨酸连接酶 (Glc) 催化谷胱甘肽 (GSH) 生物合成中的第一个和限速步骤。来自Gclm (-/-) 小鼠的CGNs的GSH水平非常低,并且对DomA诱导的毒性的敏感性比来自Gclm (/) 小鼠的CGNs高10倍。GSH乙酯降低,而Gcl抑制剂丁硫氨酸亚砜肟增加了DomA毒性。alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic/海藻酸盐受体和N-甲基-D-天冬氨酸 (NMDA) 受体的拮抗剂阻断了DomA毒性,并且NMDA受体被DomA诱导的l-谷氨酸释放激活。CGNs对DomA毒性的敏感性差异不是由于离子型谷氨酸受体的表达差异所致,这在两种基因型中钙反应和L-谷氨酸释放相似。钙螯合剂和几种抗氧化剂拮抗DomA诱导的毒性。DomA导致细胞GSH迅速下降,这先于毒性,并且下降主要是由于DomA诱导的GSH外排。DomA还引起了氧化应激的增加,如活性氧种类和脂质过氧化的增加所表明的,这是在GSH外排之后。两种基因型的星形胶质细胞均对DomA毒性具有抗性,并且对DomA的钙反应减弱,并且缺乏DomA诱导的L-谷氨酸释放。由于人类GCLM基因的多态性与低GSH水平相关,因此此类个体以及具有导致GSH缺乏的遗传条件或环境暴露的其他个体可能更容易受到DomA诱导的神经毒性的影响。

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