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Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways

Autism is complex and multifactorial, and is one of the fastest growing neurodevelopmental disorders. Canagliflozin (Cana) is an antidiabetic drug that exhibits neuroprotective properties in various neurodegenerative syndromes. This study investigated the possible protective effect of Cana against t...

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Autores principales: Elgamal, Mariam A., Khodeer, Dina M., Abdel-Wahab, Basel A., Ibrahim, Ibrahim Abdel Aziz, Alzahrani, Abdullah R., Moustafa, Yasser M., Ali, Azza A., El-Sayed, Norhan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9992196/
https://www.ncbi.nlm.nih.gov/pubmed/36909191
http://dx.doi.org/10.3389/fphar.2023.1113966
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author Elgamal, Mariam A.
Khodeer, Dina M.
Abdel-Wahab, Basel A.
Ibrahim, Ibrahim Abdel Aziz
Alzahrani, Abdullah R.
Moustafa, Yasser M.
Ali, Azza A.
El-Sayed, Norhan M.
author_facet Elgamal, Mariam A.
Khodeer, Dina M.
Abdel-Wahab, Basel A.
Ibrahim, Ibrahim Abdel Aziz
Alzahrani, Abdullah R.
Moustafa, Yasser M.
Ali, Azza A.
El-Sayed, Norhan M.
author_sort Elgamal, Mariam A.
collection PubMed
description Autism is complex and multifactorial, and is one of the fastest growing neurodevelopmental disorders. Canagliflozin (Cana) is an antidiabetic drug that exhibits neuroprotective properties in various neurodegenerative syndromes. This study investigated the possible protective effect of Cana against the valproic acid (VPA)-induced model of autism. VPA was injected subcutaneously (SC) into rat pups at a dose of 300 mg/kg, twice daily on postnatal day-2 (PD-2) and PD-3, and once on PD-4 to induce an autism-like syndrome. Graded doses of Cana were administered (5 mg/kg, 7.5 mg/kg, and 10 mg/kg, P.O.) starting from the first day of VPA injections and continued for 21 days. At the end of the experiment, behavioral tests and histopathological alterations were assessed. In addition, the gene expression of peroxisome proliferator-activated receptor γ (PPAR γ), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase (PDK), cellular myeloctomatosis (c-Myc) with protein expression of glucose transporter-1 (GLUT-1), phosphatase and tensin homolog (PTEN), and level of acetylcholine (ACh) were determined. Treatment with Cana significantly counteracted histopathological changes in the cerebellum tissues of the brain induced by VPA. Cana (5 mg/kg, 7.5 mg/kg, and 10 mg/kg) improved sociability and social preference, enhanced stereotypic behaviors, and decreased hyperlocomotion activity, in addition to its significant effect on the canonical Wnt/β-catenin pathway via the downregulation of gene expression of LDHA (22%, 64%, and 73% in cerebellum tissues with 51%, 60%, and 75% in cerebrum tissues), PDK (27%, 50%, and 67% in cerebellum tissues with 34%, 66%, and 77% in cerebrum tissues), c-Myc (35%, 44%, and 72% in cerebellum tissues with 19%, 58%, and 79% in cerebrum tissues), protein expression of GLUT-1 (32%, 48%, and 49% in cerebellum tissues with 30%, 50%, and 54% in cerebrum tissues), and elevating gene expression of PPAR-γ (2, 3, and 4 folds in cerebellum tissues with 1.5, 3, and 9 folds in cerebrum tissues), protein expression of PTEN (2, 5, and 6 folds in cerebellum tissues with 6, 6, and 10 folds in cerebrum tissues), and increasing the ACh levels (4, 5, and 7 folds) in brain tissues. The current study confirmed the ameliorating effect of Cana against neurochemical and behavioral alterations in the VPA-induced model of autism in rats.
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spelling pubmed-99921962023-03-09 Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways Elgamal, Mariam A. Khodeer, Dina M. Abdel-Wahab, Basel A. Ibrahim, Ibrahim Abdel Aziz Alzahrani, Abdullah R. Moustafa, Yasser M. Ali, Azza A. El-Sayed, Norhan M. Front Pharmacol Pharmacology Autism is complex and multifactorial, and is one of the fastest growing neurodevelopmental disorders. Canagliflozin (Cana) is an antidiabetic drug that exhibits neuroprotective properties in various neurodegenerative syndromes. This study investigated the possible protective effect of Cana against the valproic acid (VPA)-induced model of autism. VPA was injected subcutaneously (SC) into rat pups at a dose of 300 mg/kg, twice daily on postnatal day-2 (PD-2) and PD-3, and once on PD-4 to induce an autism-like syndrome. Graded doses of Cana were administered (5 mg/kg, 7.5 mg/kg, and 10 mg/kg, P.O.) starting from the first day of VPA injections and continued for 21 days. At the end of the experiment, behavioral tests and histopathological alterations were assessed. In addition, the gene expression of peroxisome proliferator-activated receptor γ (PPAR γ), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase (PDK), cellular myeloctomatosis (c-Myc) with protein expression of glucose transporter-1 (GLUT-1), phosphatase and tensin homolog (PTEN), and level of acetylcholine (ACh) were determined. Treatment with Cana significantly counteracted histopathological changes in the cerebellum tissues of the brain induced by VPA. Cana (5 mg/kg, 7.5 mg/kg, and 10 mg/kg) improved sociability and social preference, enhanced stereotypic behaviors, and decreased hyperlocomotion activity, in addition to its significant effect on the canonical Wnt/β-catenin pathway via the downregulation of gene expression of LDHA (22%, 64%, and 73% in cerebellum tissues with 51%, 60%, and 75% in cerebrum tissues), PDK (27%, 50%, and 67% in cerebellum tissues with 34%, 66%, and 77% in cerebrum tissues), c-Myc (35%, 44%, and 72% in cerebellum tissues with 19%, 58%, and 79% in cerebrum tissues), protein expression of GLUT-1 (32%, 48%, and 49% in cerebellum tissues with 30%, 50%, and 54% in cerebrum tissues), and elevating gene expression of PPAR-γ (2, 3, and 4 folds in cerebellum tissues with 1.5, 3, and 9 folds in cerebrum tissues), protein expression of PTEN (2, 5, and 6 folds in cerebellum tissues with 6, 6, and 10 folds in cerebrum tissues), and increasing the ACh levels (4, 5, and 7 folds) in brain tissues. The current study confirmed the ameliorating effect of Cana against neurochemical and behavioral alterations in the VPA-induced model of autism in rats. Frontiers Media S.A. 2023-02-22 /pmc/articles/PMC9992196/ /pubmed/36909191 http://dx.doi.org/10.3389/fphar.2023.1113966 Text en Copyright © 2023 Elgamal, Khodeer, Abdel-Wahab, Ibrahim, Alzahrani, Moustafa, Ali and El-Sayed. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Elgamal, Mariam A.
Khodeer, Dina M.
Abdel-Wahab, Basel A.
Ibrahim, Ibrahim Abdel Aziz
Alzahrani, Abdullah R.
Moustafa, Yasser M.
Ali, Azza A.
El-Sayed, Norhan M.
Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways
title Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways
title_full Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways
title_fullStr Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways
title_full_unstemmed Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways
title_short Canagliflozin alleviates valproic acid-induced autism in rat pups: Role of PTEN/PDK/PPAR-γ signaling pathways
title_sort canagliflozin alleviates valproic acid-induced autism in rat pups: role of pten/pdk/ppar-γ signaling pathways
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9992196/
https://www.ncbi.nlm.nih.gov/pubmed/36909191
http://dx.doi.org/10.3389/fphar.2023.1113966
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