Int J Physiol Pathophysiol Pharmacol 2010;2(2):137-147
Original Article RIP1 kinase mediates arachidonic acid-induced oxidative death of oligodendrocyte precursors
Sunja Kim, Laila Dayani, Paul A Rosenberg, Jianrong Li
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843, USA; F.M. Kirby Neurology Center, Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
Received May 16, 2010, accepted June 11, 2010, available online June 12, 2010
Abstract: 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 glutathione 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 sulphoximine, 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. (IJPPP1005001).
Address all correspondence to: Jianrong Li, PhD Department of Veterinary Integrative Biosciences Texas A&M University, Mail Stop 4458 College Station, TX 77843 Tel: 979-862-7155 Fax: 979-847-8981 Email: jrli@cvm.tamu.edu