Glycogen synthase kinase 3beta inhibitor Chir025 reduces neuronal death resulting from oxygen-glucose deprivation, glutamate excitotoxicity, and cerebral ischemia.
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.
Kelly
Stephen
S
Department of Neurosurgery, Stanford University, CA 94305-5487, USA.
Zhao
Heng
H
Hua Sun
Guo
G
Cheng
Danye
D
Qiao
Yanli
Y
Luo
Jian
J
Martin
Kathleen
K
Steinberg
Gary K
GK
Harrison
Stephen D
SD
Yenari
Midori A
MA
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
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