Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation
Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation
复制标题
DOI：
10.1111/j.1471-4159.2007.04487.x
复制
发表时间：
2007-06-01
影响因子：
4.7
通讯作者：
Beggs, Marjorie L.
中科院分区：
文献类型：
--
作者：
Barger, Steven W.;Goodwin, Mary E.;Beggs, Marjorie L.
当受到促炎刺激激活时，小胶质细胞会释放大量的谷氨酸，越来越多的证据表明这在神经炎症期间会导致神经元损伤。先前的研究表明Xc交换系统起作用，它是一种氨基酸转运体，可将谷氨酸与胱氨酸进行逆向转运。由于胱氨酸用于合成谷胱甘肽（GSH），我们假设谷氨酸的释放是呼吸爆发消耗GSH的间接结果，呼吸爆发会从NADPH氧化酶产生超氧化物。脂多糖触发的小胶质细胞谷氨酸释放可被氯化二亚苯基碘鎓和夹竹桃麻素（NADPH氧化酶的抑制剂）阻断。这种谷氨酸释放也可被维生素E阻断，并可由脂质过氧化产物4 - 羟基壬烯醛和丙烯醛引发，这表明脂质过氧化对GSH有重要需求。尽管NADPH氧化酶抑制剂也抑制了亚硝酸盐的积累，但维生素E没有；此外，谷氨酸释放在很大程度上不受一氧化氮供体、一氧化氮合酶抑制剂或基因表达变化的影响。这些发现表明，神经炎症的神经退行性后果在很大程度上可能是由氧化应激转化为兴奋性毒性应激导致的。这种现象涉及一系列由程序性氧化应激和由此产生的大量氨基酸转运引发的生化事件。实际上，抗氧化剂的一些神经保护作用可能是由于对这些事件的干扰，而不是对神经元氧化的直接保护。
When activated by proinflammatory stimuli, microglia release substantial levels of glutamate, and mounting evidence suggests this contributes to neuronal damage during neuroinflammation. Prior studies indicated a role for the Xc exchange system, an amino acid transporter that antiports glutamate for cystine. Because cystine is used for synthesis of glutathione (GSH) synthesis, we hypothesized that glutamate release is an indirect consequence of GSH depletion by the respiratory burst, which produces superoxide from NADPH oxidase. Microglial glutamate release triggered by lipopolysaccharide was blocked by diphenylene iodonium chloride and apocynin, inhibitors of NADPH oxidase. This glutamate release was also blocked by vitamin E and elicited by lipid peroxidation products 4-hydroxynonenal and acrolein, suggesting that lipid peroxidation makes crucial demands on GSH. Although NADPH oxidase inhibitors also suppressed nitrite accumulation, vitamin E did not; moreover, glutamate release was largely unaffected by nitric oxide donors, inhibitors of nitric oxide synthase, or changes in gene expression. These findings indicate that a considerable degree of the neurodegenerative consequences of neuroinflammation may result from conversion of oxidative stress to excitotoxic stress. This phenomenon entails a biochemical chain of events initiated by a programmed oxidative stress and resultant mass-action amino acid transport. Indeed, some of the neuroprotective effects of antioxidants may be due to interference with these events rather than direct protection against neuronal oxidation.