Back to Search
Start Over
Glycogen synthase kinase 3beta inhibitor Chir025 reduces neuronal death resulting from oxygen-glucose deprivation, glutamate excitotoxicity, and cerebral ischemia.
- Source :
-
Experimental neurology [Exp Neurol] 2004 Aug; Vol. 188 (2), pp. 378-86. - Publication Year :
- 2004
-
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.
- Subjects :
- Animals
Brain Chemistry
Brain Ischemia pathology
Brain Ischemia physiopathology
Caspases metabolism
Cell Death drug effects
Cell Hypoxia
Cells, Cultured
Cytosol metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors analysis
Glucose deficiency
Glucose metabolism
Glutamic Acid toxicity
Glycogen Synthase Kinase 3 metabolism
Glycogen Synthase Kinase 3 beta
In Situ Nick-End Labeling
Male
Mice
Neurons pathology
Neuroprotective Agents pharmacology
Proto-Oncogene Proteins c-bcl-2 metabolism
Rats
Rats, Sprague-Dawley
Brain Ischemia drug therapy
Enzyme Inhibitors pharmacology
Glycogen Synthase Kinase 3 antagonists & inhibitors
Neurons drug effects
Neurons metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0014-4886
- Volume :
- 188
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 15246837
- Full Text :
- https://doi.org/10.1016/j.expneurol.2004.04.004