RIP1 kinase mediates arachidonic acid-induced oxidative death of oligodendrocyte precursors

International Journal of Physiology, Pathophysiology and Pharmacology

Paul A Rosenberg¹  Laila Dayani¹  Jianrong Li¹  Sunja Kim¹ 

关键词: Arachidonic acid;    oligodendrocyte precursors;    programmed cell death;    oxidative stress;    RIP1;    periventricu-lar leukomalacia;    necroptosis;    necrosis;   

DOI  :  

学科分类：生理学与病理学

来源: e-Century Publishing Corporation

【 摘 要 】

Oxidative damage is implicated in many neurological disorders including ischemic cerebral white matter injury. Oligodendrocyte precursors (preOLs) are intrinsically highly susceptible to various forms of oxidative stress. Here we report the identification of RIP1 kinase as a signaling molecule that mediates arachidonic acid- and glu-tathione depletion-induced oxidative death of preOLs. Blockade of RIP1 kinase activity with the specific allosteric inhibitor, necrostatin-1, rescued preOLs from arachidonic acid, cystine deprivation, and buthionine sulfoximine, but not hydrogen peroxide, induced necrosis. Arachidonic acid triggered robust production of reactive oxygen species (ROS) and sustained activation of the JNK pathway in preOLs, whereas inhibition of JNK significantly prevented cell death. Treatment of cells with necrostatin-1 efficiently abolished arachidonic acid-induced ROS production and JNK activation, indicating that RIP1 kinase activation is an upstream event. This study provides the first evidence that RIP1 kinase may play an active role in arachidonic acid- and glutathione depletion-mediated oxidative damage and suggests the therapeutic potential of necrostatin-1 in protecting undifferentiated OLs against oxidative injury.

【 授权许可】

Unknown