TY - JOUR T1 - GSK-3 as a Target for Lithium-Induced Neuroprotection Against Excitotoxicity in Neuronal Cultures and Animal Models of Ischemic Stroke. AU - Chuang,De-Maw, AU - Wang,Zhifei, AU - Chiu,Chi-Tso, Y1 - 2011/08/09/ PY - 2011/06/28/received PY - 2011/07/24/accepted PY - 2011/9/3/entrez PY - 2011/9/3/pubmed PY - 2011/9/3/medline KW - cerebral ischemia KW - excitotoxicity KW - glycogen synthase kinase-3 KW - lithium KW - mesenchymal stem cells SP - 15 EP - 15 JF - Frontiers in molecular neuroscience JO - Front Mol Neurosci VL - 4 N2 - The mood stabilizer lithium inhibits glycogen synthase kinase-3 (GSK-3) directly or indirectly by enhancing serine phosphorylation of both α and β isoforms. Lithium robustly protected primary brain neurons from glutamate-induced excitotoxicity; these actions were mimicked by other GSK-3 inhibitors or silencing/inhibiting GSK-3α and/or β isoforms. Lithium rapidly activated Akt to enhance GSK-3 serine phosphorylation and to block glutamate-induced Akt inactivation. Lithium also up-regulated Bcl-2 and suppressed glutamate-induced p53 and Bax. Induction of brain-derived neurotrophic factor (BDNF) was required for lithium's neuroprotection to occur. BDNF promoter IV was activated by GSK-3 inhibition using lithium or other drugs, or through gene silencing/inactivation of either isoform. Further, lithium's neuroprotective effects were associated with inhibition of NMDA receptor-mediated calcium influx and down-stream signaling. In rodent ischemic models, post-insult treatment with lithium decreased infarct volume, ameliorated neurological deficits, and improved functional recovery. Up-regulation of heat-shock protein 70 and Bcl-2 as well as down-regulation of p53 likely contributed to lithium's protective effects. Delayed treatment with lithium improved functional MRI responses, which was accompanied by enhanced angiogenesis. Two GSK-3-regulated pro-angiogenic factors, matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor were induced by lithium. Finally, lithium promoted migration of mesenchymal stem cells (MSCs) by up-regulation of MMP-9 through GSK-3β inhibition. Notably, transplantation of lithium-primed MSCs into ischemic rats enhanced MSC migration to the injured brain regions and improved the neurological performance. Several other GSK-3 inhibitors have also been reported to be beneficial in rodent ischemic models. Together, GSK-3 inhibition is a rational strategy to combat ischemic stroke and other excitotoxicity-related brain disorders. SN - 1662-5099 UR - https://www.unboundmedicine.com/medline/citation/21886605/GSK_3_as_a_Target_for_Lithium_Induced_Neuroprotection_Against_Excitotoxicity_in_Neuronal_Cultures_and_Animal_Models_of_Ischemic_Stroke_ L2 - https://doi.org/10.3389/fnmol.2011.00015 DB - PRIME DP - Unbound Medicine ER -