Inactivation of glycogen synthase kinase-3beta protects against kainic acid-induced neurotoxicity in vivo.
Many neurodegenerative diseases involve oxidative stress and excitotoxic cell death. In an attempt to further elucidate the signal transduction pathways involved in the cell death/cell survival associated with excitotoxicity, we have used an in vivo model of excitotoxicity employing kainic acid (KA)-induced neurotoxicity. Here, we show that extracellular signal-related kinase (ERK) 2, but not ERK 1, is phosphorylated and thereby activated in the hippocampus and cerebellum of kainic acid-treated mice. Phosphorylation and hence inactivation of glycogen synthase kinase 3beta (GSK-3beta), a general survival factor, is often a downstream consequence of mitogen-activated protein kinase pathway activation. Indeed, GSK-3beta phosphorylation occurred in response to kainic acid exclusively in the affected hippocampus, but not as a consequence of ERK activation. This may represent a compensatory attempt at self-protection by the cells in this particular brain region. A role for GSK-3beta inhibition in cell survival was further supported by the fact that pharmacological inhibition of GSK-3beta using lithium chloride was protective against kainic acid-induced excitotoxicity in hippocampal slice cultures. This work supports a role for GSK-3beta in cell death in response to excitotoxins in vivo and further confirms that GSK-3beta plays a role in cell death/cell survival pathways.
Department of Pathobiochemistry, Johannes Gutenberg University, Mainz, Germany.
Sharon
S
Goodenough
Sabine
S
Conrad
Thomas
T
Skutella
Christian
C
Behl
D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D002070:Butadienes / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D007608:Kainic Acid; D018021:Lithium Chloride / Q000627:therapeutic use; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control*; D009570:Nitriles / Q000627:therapeutic use; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D013778:Tetrazolium Salts; D013844:Thiazoles; C113580:U 0126; D014443:Tyrosine; D012694:Serine; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D038362:Glycogen Synthase Kinase 3; C022616:thiazolyl blue; D018021:Lithium Chloride; D007608:Kainic Acid