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

:这项研究利用缺乏谷氨酸-半胱氨酸连接酶(Gclm)修饰子亚基的小鼠的小脑颗粒神经元(CGNs),研究了细胞抗氧化剂防御机制在调节多摩酸(DomA)的神经毒性中的作用。谷氨酸-半胱氨酸连接酶(Glc)催化谷胱甘肽(GSH)生物合成中的第一步和限速步骤。来自Gclm(/)小鼠的CGNs的GSH水平非常低,对DomA诱导的毒性的敏感性比来自Gclm(/)小鼠的CGNs高10倍。 GSH乙酯减少,而Gcl抑制剂丁硫氨酸亚砜亚胺增加DomA毒性。 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸/海藻酸酯受体和N-甲基-D-天冬氨酸(NMDA)受体的拮抗剂可阻断DomA毒性,并且NMDA受体被DomA诱导的L-谷氨酸激活。释放。 CGN对DomA毒性的敏感性差异不归因于离子型谷氨酸受体的差异表达,这由两种基因型的相似钙反应和L-谷氨酸释放所证明。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,而毒性先于毒性下降,而下降主要归因于DomA诱导的GSH外排。 DomA还引起氧化应激的增加,如活性氧和脂质过氧化作用的增加所表明的,这是GSH流出后的结果。两种基因型的星形胶质细胞都对DomA毒性有抵抗力,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,因此此类个体以及遗传条件或环境暴露导致GSH缺乏的其他个体可能更容易受到DomA诱导的神经毒性。

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