Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase
Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase
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DOI：
10.1042/bst0351119
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发表时间：
2007-11-01
影响因子：
3.9
通讯作者：
Brown, G. C.
中科院分区：
文献类型：
--
作者：
Brown, G. C.
炎症导致多种大脑病理，显然是通过神经胶质杀死神经元。炎症激活的小胶质细胞和星形胶质细胞杀死神经元的许多机制已在培养中被确定。这些包括NOS（诱导型一氧化氮合酶），其仅在炎症期间在胶质细胞中表达，以及PHOX（吞噬性NADPH氧化酶），其在小胶质细胞中发现并被炎症急性激活。神经胶质细胞中高水平的NOS表达导致（i）NO（一氧化氮）抑制神经元呼吸，导致神经元去极化和谷氨酸释放，随后是兴奋性毒性，以及（ii）星形胶质细胞通过钙依赖性囊泡释放释放谷氨酸。缺氧与iNOS表达强烈协同，通过机制（i）诱导神经元死亡，因为NO抑制细胞色素氧化酶与氧竞争。PHOX的激活（通过细胞因子、β-淀粉样蛋白、朊病毒蛋白、ATP或花生四烯酸）导致小胶质细胞增殖和炎症激活;因此PHOX是炎症的关键调节因子。单独激活PHOX不会导致死亡，但当与表达的iNOS结合时，通过过氧亚硝酸盐的产生导致广泛的神经元死亡。
Inflammation contributes to a wide variety of brain pathologies, apparently via glia killing neurons. A number of mechanisms by which inflammatory-activated microglia and astrocytes kill neurons have been identified in culture. These include NOS (inducible nitric oxide synthase), which is expressed in glia only during inflammation, and PHOX (phagocytic NADPH oxidase) found in microglia and acutely activated by inflammation. High levels of NOS expression in glia cause (i) NO (nitric oxide) inhibition of neuronal respiration, resulting in neuronal depolarization and glutamate release, followed by excitotoxicity, and (ii) glutamate release from astrocytes via calcium-dependent vesicular release. Hypoxia strongly synergizes with iNOS expression to induce neuronal death via mechanism (i), because NO inhibits cytochrome oxidase in competition with oxygen. Activation of PHOX (by cytokines, beta-amyloid, prion protein, ATP or arachidonate) causes microglial proliferation and inflammatory activation; thus PHOX is a key regulator of inflammation. Activation of PHOX alone causes no death, but when combined with expressed iNOS results in extensive neuronal death via peroxynitrite production.