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J Biol Chem. 2015 Nov 20;290(47):28540-58. doi: 10.1074/jbc.M115.652586. Epub 2015 Sep 29.

Ethosuximide Induces Hippocampal Neurogenesis and Reverses Cognitive Deficits in an Amyloid-β Toxin-induced Alzheimer Rat Model via the Phosphatidylinositol 3-Kinase (PI3K)/Akt/Wnt/β-Catenin Pathway.

Author information

  • 1From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, the Academy of Scientific and Innovative Research, and.
  • 2From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group.
  • 3the Systems Toxicology and Health Risk Assessment Group, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Toxicology Research, 80 MG Marg, Lucknow 226001, India.
  • 4the Department of Pharmacology, Centre of Excellence for Translational Medicine; University of Tartu, Tartu 50411, Estonia, and.
  • 5the CSIR-Institute of Genomics and Integrative Biology, Sukhdev Vihar, Mathura Road, 110025 New Delhi, India abhaysharma@igib.res.in.
  • 6From the Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, the Academy of Scientific and Innovative Research, and rajnish@iitr.res.in.

Abstract

Neurogenesis involves generation of new neurons through finely tuned multistep processes, such as neural stem cell (NSC) proliferation, migration, differentiation, and integration into existing neuronal circuitry in the dentate gyrus of the hippocampus and subventricular zone. Adult hippocampal neurogenesis is involved in cognitive functions and altered in various neurodegenerative disorders, including Alzheimer disease (AD). Ethosuximide (ETH), an anticonvulsant drug is used for the treatment of epileptic seizures. However, the effects of ETH on adult hippocampal neurogenesis and the underlying cellular and molecular mechanism(s) are yet unexplored. Herein, we studied the effects of ETH on rat multipotent NSC proliferation and neuronal differentiation and adult hippocampal neurogenesis in an amyloid β (Aβ) toxin-induced rat model of AD-like phenotypes. ETH potently induced NSC proliferation and neuronal differentiation in the hippocampus-derived NSC in vitro. ETH enhanced NSC proliferation and neuronal differentiation and reduced Aβ toxin-mediated toxicity and neurodegeneration, leading to behavioral recovery in the rat AD model. ETH inhibited Aβ-mediated suppression of neurogenic and Akt/Wnt/β-catenin pathway gene expression in the hippocampus. ETH activated the PI3K·Akt and Wnt·β-catenin transduction pathways that are known to be involved in the regulation of neurogenesis. Inhibition of the PI3K·Akt and Wnt·β-catenin pathways effectively blocked the mitogenic and neurogenic effects of ETH. In silico molecular target prediction docking studies suggest that ETH interacts with Akt, Dkk-1, and GSK-3β. Our findings suggest that ETH stimulates NSC proliferation and differentiation in vitro and adult hippocampal neurogenesis via the PI3K·Akt and Wnt·β-catenin signaling.

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

cell differentiation; cell proliferation; ethosuximide; hippocampus; neural stem cell (NSC); neurodegeneration; neurodegenerative disease; neurogenesis; neuron; neuroprotection

PMID:
26420483
[PubMed - indexed for MEDLINE]
PMCID:
PMC4653709
[Available on 2016-11-20]
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