SY33-2 * NEUROPROTECTIVE SIGNALING PATHWAY VIA NICOTINIC RECEPTORS

Abstract

Introduction. Our previous data showed that treatment of nicotine or donepezil prevented glutamate-induced cytotoxicity via nicotinic receptors (nAChRs) using primary culture of rat cortical neurons. The present study was performed to investigate the detailed mechanisms of nAChRs-mediated neuroprotection, especially involvement of glycogen synthase kinase-3β(GSK3 β ) as a downstream of PI3K-Akt pathway. Methods. Neuronal death was determined by LDH release assay in rat primary culture of cerebral cortex. Phosphorylation of GSK3β and the expression level of β-catenin were measured by western blot analysis. Results and Conclusion. Donepezil induced the Ser9-phosphorylation of GSK3β in rat cultured cortical neurons. LY294002, an inhibitor of PI3K, prevented that phosphorylation of GSK3β. Glutamate induced the Tyr216-phosphorylation of GSK3β. Donepezil prevented glutamate-induced phosphorylation of Tyr216. Bcl-2 was upregulated by donepezil treatment, but not by SB216763, an inhibitor of GSK3β treatment. On the other hand, the expression level of β-catenin was increased by both donepezil and SB216763. These results suggested that inactivation of GSK3β as the downstream signaling of PI3K-Akt pathway play a crucial role in the nAChR-mediated neuroprotection.