title: Involvement of GSK-3β Phosphorylation Through PI3-K/Akt in Cerebral Ischemia-Induced Neurogenesis in Rats.
abstract: Glycogen synthase kinase (GSK)-3β, which is abundantly expressed in the central nervous system, regulates various cellular processes including gene expression, cell proliferation, and differentiation. However, involvement of GSK-3β in cerebral ischemia-induced endogenous neurogenesis is not yet fully understood. Appropriate strategies to prevent ischemic cell damage and subsequent severe sequelae are needed. The purpose of the present study was to determine the relationship between pathophysiological alteration of the GSK-3β signaling pathway and cerebral ischemia-induced endogenous neurogenesis in rats. Severe cerebral ischemia was produced by the injection of 700 microspheres into the right internal carotid artery of rats. We demonstrated that phosphorylation of GSK-3β at its Ser9 and that of Akt was significantly enhanced on day 7 after the cerebral ischemia, as was the number of NeuroD-positive cells. Treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor decreased the cerebral ischemia-induced phosphorylation of Akt and that of GSK-3β at its Ser9. In addition, as the protein levels of insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) were decreased, they might not have been essential for activation of the PI3-K/Akt/GSK-3β pathway after severe cerebral ischemia. Although it remains to be determined what factors activate this pathway, our results suggest that PI3K/Akt-dependent GSK-3β signaling and subsequent expression of NeuroD were involved in the neurogenesis elicited by cerebral ischemia.
authors.affiliation: Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Kisoh
authors.affiliation: Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Asada
authors.affiliation: Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Arai
authors.affiliation: Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tanonaka
authors.affiliation: Department of Applied Biochemistry, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan. takagino@toyaku.ac.jp.
authors.forename: Norio
authors.identifier: 0000-0001-5801-1050
authors.initials: N
authors.lastname: Takagi
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D008297:Male; D055495:Neurogenesis / Q000502:physiology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058539:Phosphatidylinositol 3-Kinase; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: Cerebral ischemia; GSK-3β; Neurogenesis; PI3-K/Akt