Journal
EXPERIMENTAL NEUROLOGY
Volume 188, Issue 2, Pages 378-386Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2004.04.004
Keywords
glycogen kinase synthase 3 beta; focal cerebral ischemia; oxygen-glucose deprivation; glutamate toxicity; stroke; neuroprotection
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Funding
- NINDS NIH HHS [R01 NS40516] Funding Source: Medline
- PHS HHS [R01 27292] Funding Source: Medline
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The serine/threonine kinase, glycogen synthase kinase 3beta (GSKbeta), 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 Chir-025 is neuroprotective in vitro and in vivo. First, Chir-025 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. (C) 2004 Elsevier Inc. All rights reserved.
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