Diphenyleneiodonium protects preoligodendrocytes against endotoxin-activated microglial NADPH oxidase-generated peroxynitrite in a neonatal rat model of periventricular leukomalacia
Diphenyleneiodonium protects preoligodendrocytes against endotoxin-activated microglial NADPH oxidase-generated peroxynitrite in a neonatal rat model of periventricular leukomalacia
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DOI：
10.1016/j.brainres.2012.11.017
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发表时间：
2013-01-25
期刊：
影响因子：
2.9
通讯作者：
Buzby, Jeffrey S.
中科院分区：
文献类型：
--
作者：
He, Ya-fang;Chen, Hui-jin;Buzby, Jeffrey S.
小胶质细胞活化对中枢神经系统（CNS）前少突胶质细胞（preoligodendroglial，preOL）损伤的贡献被认为是脑室周围白质软化症（PVL）发病机制的主要原因之一。本研究探讨了NADPH氧化酶（NOX）抑制剂二苯基碘鎓（DPI）对细菌脂多糖（LPS）诱导的小胶质细胞毒性的保护作用。在体外，与小胶质细胞共培养的前OL表现出增加的前OL凋亡，伴随着超氧阴离子（O-2（-））的过量产生和过氧亚硝酸盐（ONOO-）的形成后，LPS暴露。LPS还显著上调了活化的小胶质细胞NOX亚基p67-phox和gp 91-phox在质膜中的积累。发现二苯基碘鎓（DPI）（10 μ m）显著减弱这种NOX活性的上调。在体内，DPI通过皮下注射给药（1 mg/kg/天）3天至脑内注射LPS的2日龄新生Sprague-Dawley大鼠。在LPS注射后24 h内给予DPI治疗可明显减轻小胶质细胞的白色损伤，减少前OL丢失、O-2（-）生成和ONOO-形成，抑制p67-phox、gp 91-phox合成和p67-phox膜转位。这些结果表明，LPS诱导的前OL凋亡可能是由小胶质细胞源性ONOO-介导的。DPI预防了这种LPS诱导的脑损伤，最有可能是通过抑制经由NOX的ONOO-形成，从而预防了前OL损失和未成熟的白色物质损伤。(C)2012爱思唯尔有限公司版权所有。
The contribution of microglial activation to preoligodendroglial (preOL) damage in the central nervous system (CNS) is considered to be one of the principal causes of periventricular leukomalacia (PVL) pathogenesis. The present study explores the effect of diphenyleneiodonium (DPI), a NADPH oxidase (NOX) inhibitor, on protection of preOLs from bacterial lipopolysaccharide (LPS)-induced microglial toxicity in vivo and in vitro. In vitro, preOLs co-cultured with microglia exhibited increased preOL apoptosis, accompanied by overproduction of superoxide anion (O-2(-)) and the formation of peroxynitrite (ONOO-) after LPS exposure. LPS also significantly up-regulated accumulation of activated microglial NOX subunits p67-phox and gp91-phox in the plasma membrane. Diphenyleneiodonium (DPI) (10 mu m) was found to significantly attenuate up-regulation of this NOX activity. In vivo, DPI was administered (1 mg/kg/day) by subcutaneous injection for 3 days to two-day-old neonatal Sprague-Dawley rats subjected to intracerebral injection of LPS. Treatment with DPI within 24h of LPS injection significantly ameliorated white matter injury, decreasing preOL loss, O-2(-) generation, and ONOO- formation, and inhibiting p67-phox, gp91-phox synthesis and p67phox membrane translocation in microglia. These results indicated that LPS-induced preOL apoptosis may have been mediated by microglia-derived ONOO-. DPI prevented this LPS-induced brain injury, most likely by inhibiting ONOO- formation via NOX, thereby preventing preOL loss and immature white matter injury. (C) 2012 Elsevier B.V. All rights reserved.