Involvement of GSK-3\u03b2 Phosphorylation Through PI3-K/Akt in Cerebral Ischemia-Induced Neurogenesis in Rats

Keishi Kisoh,Hideki Hayashi,Norio Takagi,Bo Yuan,Kouichi Tanonaka,Mayumi Asada,Tsuyoshi Itoh,Miho Arai

doi:10.1007/s12035-016-0290-8

Keishi Kisoh, Hideki Hayashi + Show 6 more

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https://doi.org/10.1007/s12035-016-0290-8

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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.

Highlights

Glycogen synthase kinase-3 (GSK-3), a serine/threonine (Ser/Thr) kinase, was identified some time ago as an enzyme that phosphorylates glycogen synthase to render it inactive [1]
2 Department of Molecular and Cellular Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan 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
We demonstrated that Microsphereinduced cerebral embolism (ME) increased proliferation of cells that expressed nestin, a neural progenitor marker, and DCX, a microtubule-associated protein found in migrating immature neurons

Summary

Introduction

Glycogen synthase kinase-3 (GSK-3), a serine/threonine (Ser/Thr) kinase, was identified some time ago as an enzyme that phosphorylates glycogen synthase to render it inactive [1]. GSK-3β is abundantly expressed in the mammalian central nervous system and regulates various cellular processes including gene expression, cell proliferation, and differentiation. Β-Catenin is a signaling molecule that is phosphorylated by GSK-3β, resulting in its degradation by the ubiquitin-proteasome system. Inactivated GSK-3β, which is phosphorylated at its Ser, inhibits this proteasomal degradation of β-catenin. Β-catenin accumulates in the cytosol and is translocated into the nucleus, where it contributes to gene expression related to cell proliferation and differentiation [2, 3]. NeuroD, which is a proneural basic helix-loop-helix (bHLH) transcription factor, promotes premature cell cycle exit and differentiation into neural progenitor cells, indicating a differentiation factor [7, 8]. Some studies have indicated that NeuroD is

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