NEUROPHARMACOLOGY AND NEUROTOXICOLOGYInhibition of glycogen synthase kinase-3 protects cells from intrinsic but not extrinsic oxidative stressKing, Taj D.; Jope, Richard S.CAAuthor Information Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA CACorresponding Author: [email protected] Received 19 January 2005; accepted 7 February 2005 NeuroReport: April 25, 2005 - Volume 16 - Issue 6 - p 597-601 Buy Abstract Oxidative stress is linked to neuronal dysfunction and death in many diseases. Glycogen synthase kinase-3 often promotes apoptosis, so this investigation tested whether glycogen synthase kinase-3 is linked to oxidative stress-induced apoptosis. Both intrinsic oxidative stress induced by the mitochondrial inhibitor rotenone and extrinsic oxidative stress induced by exogenously added H2O2 activated Bax, caspase-2, and caspase-3 in human neuroblastoma SH-SY5Y cells. Inhibitors of glycogen synthase kinase-3 blocked rotenone-induced, but not H2O2-induced, activation of both caspases, but not Bax activation. Thus, glycogen synthase kinase-3 is an important component of intrinsic oxidative stress-induced apoptosis that acts downstream of mitochondrial Bax activation, and there are substantial differences in the role of glycogen synthase kinase-3, and lithium's effects, in apoptotic signaling induced by intrinsic and extrinsic oxidative stress. © 2005 Lippincott Williams & Wilkins, Inc.