IJPPP Copyright © 2009-All rights reserved. Published by e-Century Publishing Corporation, Madison, WI 53711
Int J Physiol Pathophysiol Pharmacol 2010;2(2):137-147

Original Article
RIP1 kinase mediates arachidonic acid-induced oxidative death of oligodendrocyte

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).

Key words: Arachidonic acid, oligodendrocyte precursors, programmed cell death, oxidative stress, RIP1, periventricular leukomalacia,
necroptosis, necrosis

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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