title: 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.
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.
authors.affiliation: Developmental Toxicology Laboratory, 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; Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Toxicology Research, 80 MG Marg, Lucknow 226001, India.
authors.forename: Shashi Kant
authors.initials: SK
authors.lastname: Tiwari
authors.affiliation: Developmental Toxicology Laboratory, 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; Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Toxicology Research, 80 MG Marg, Lucknow 226001, India.
authors.forename: Brashket
authors.initials: B
authors.lastname: Seth
authors.affiliation: Developmental Toxicology Laboratory, 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; Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Toxicology Research, 80 MG Marg, Lucknow 226001, India.
authors.forename: Swati
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Developmental Toxicology Laboratory, 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; Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Toxicology Research, 80 MG Marg, Lucknow 226001, India.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Yadav
authors.affiliation: Developmental Toxicology Laboratory, 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.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Karmakar
authors.affiliation: 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.
authors.forename: Shailendra Kumar
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Department of Pharmacology, Centre of Excellence for Translational Medicine; University of Tartu, Tartu 50411, Estonia.
authors.forename: Vinay
authors.initials: V
authors.lastname: Choubey
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Sukhdev Vihar, Mathura Road, 110025 New Delhi, India. Electronic address: abhaysharma@igib.res.in.
authors.forename: Abhay
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Developmental Toxicology Laboratory, 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; Academy of Scientific and Innovative Research, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Toxicology Research, 80 MG Marg, Lucknow 226001, India.
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Chaturvedi
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003072:Cognition Disorders / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism; D004195:Disease Models, Animal; D005013:Ethosuximide / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051153:Wnt Proteins; D051176:beta Catenin; D005013:Ethosuximide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: cell differentiation; cell proliferation; ethosuximide; hippocampus; neural stem cell (NSC); neurodegeneration; neurodegenerative disease; neurogenesis; neuron; neuroprotection