title: Glycogen synthase kinase 3beta inhibitor Chir025 reduces neuronal death resulting from oxygen-glucose deprivation, glutamate excitotoxicity, and cerebral ischemia.
abstract: The serine/threonine kinase, glycogen synthase kinase 3beta (GSK3beta), is abundant in CNS and is neuron specific. GSK3beta plays a pivotal role in the regulation of numerous cellular functions. GSK3beta phosphorylates and thereby regulates many metabolic, signaling, and structural proteins which can influence cell survival. Increased GSK3beta correlates with increased cell death, whereas reduced GSK3beta expression correlates with increased cell survival. We report that the GSK3beta inhibitor Chir025 is neuroprotective in vitro and in vivo. First, Chir025 reduced cultured hippocampal neuron death following glutamate exposure by 15-20% versus vehicle-treated controls. Second, Chir025 significantly reduced cultured cortical neuron death following oxygen-glucose deprivation (OGD) by approximately 50%. Third, Chir025 reduced infarct size following focal cerebral ischemia by nearly 20%. There were no significant differences in the number of TUNEL-positive neurons or in caspase-3 and -9 activities between Chir025- and vehicle-treated rats, although Chir025 elevated cytosolic Bcl-2 expression. These data show that Chir025-mediated inhibition of GSK3beta is neuroprotective and that the mechanism is probably not anti-apoptotic.
authors.affiliation: Department of Neurosurgery, Stanford University, CA 94305-5487, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kelly
authors.forename: Heng
authors.initials: H
authors.lastname: Zhao
authors.forename: Guo
authors.initials: G
authors.lastname: Hua Sun
authors.forename: Danye
authors.initials: D
authors.lastname: Cheng
authors.forename: Yanli
authors.initials: Y
authors.lastname: Qiao
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Kathleen
authors.initials: K
authors.lastname: Martin
authors.forename: Gary K
authors.initials: GK
authors.lastname: Steinberg
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Harrison
authors.forename: Midori A
authors.initials: MA
authors.lastname: Yenari
mesh_terms: D000818:Animals; D001923:Brain Chemistry; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000032:analysis / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D018698:Glutamic Acid; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D020169:Caspases; D005947:Glucose