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Metformin Protects From Rotenone–Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis

Parkinson’s disease (PD) is a neurodegenerative disease that affects substantia nigra dopamine neurons. Many studies have documented the role of oxidative stress and angiogenesis in the pathogenesis of PD. Metformin (MTF) is an antidiabetic medication and AMP-activated protein kinase (AMPK) regulato...

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Autores principales: El-Ghaiesh, Sabah H., Bahr, Hoda I., Ibrahiem, Afaf T., Ghorab, Doaa, Alomar, Suliman Y., Farag, Noha E., Zaitone, Sawsan A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314970/
https://www.ncbi.nlm.nih.gov/pubmed/32625061
http://dx.doi.org/10.3389/fnmol.2020.00084
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author El-Ghaiesh, Sabah H.
Bahr, Hoda I.
Ibrahiem, Afaf T.
Ghorab, Doaa
Alomar, Suliman Y.
Farag, Noha E.
Zaitone, Sawsan A.
author_facet El-Ghaiesh, Sabah H.
Bahr, Hoda I.
Ibrahiem, Afaf T.
Ghorab, Doaa
Alomar, Suliman Y.
Farag, Noha E.
Zaitone, Sawsan A.
author_sort El-Ghaiesh, Sabah H.
collection PubMed
description Parkinson’s disease (PD) is a neurodegenerative disease that affects substantia nigra dopamine neurons. Many studies have documented the role of oxidative stress and angiogenesis in the pathogenesis of PD. Metformin (MTF) is an antidiabetic medication and AMP-activated protein kinase (AMPK) regulator that has shown antioxidant and antiangiogenic properties in many disorders. The aim of this study is to investigate the neuroprotective effect of MTF in a mouse model of rotenone-prompted PD with a highlight on its influence on the AMPK/forkhead box transcription factor O3 (FOXO3) pathway and striatal angiogenesis. In the running study, PD was induced in mice using repeated doses of rotenone and concomitantly treated with MTF 100 or 200 mg/kg/day for 18 days. Rotarod and pole tests were used to examine the animals’ motor functionality. After that, animals were sacrificed, and brains were isolated and processed for immunohistochemical investigations or biochemical analyses. Oxidant stress and angiogenic markers were measured, including reduced glutathione, malondialdehyde, the nuclear factor erythroid 2–related factor 2 (Nrf2), hemoxygenase-1, thioredoxin, AMPK, FOXO3, and vascular endothelial growth factor (VEGF). Results indicated that MTF improved animals’ motor function, improved striatal glutathione, Nrf2, hemoxygenase-1, and thioredoxin. Furthermore, MTF upregulated AMPK-FOXO3 proteins and reduced VEGF and cleaved caspase 3. MTF also increased the number of tyrosine hydroxylase (TH)–stained neurons in the substantia nigra neurons and in striatal neuronal terminals. This study is the first to highlight that the neuroprotective role of MTF is mediated through activation of AMPK-FOXO3 signaling and inhibition of the proangiogenic factor, VEGF. Further studies are warranted to confirm this mechanism in other models of PD and neurodegenerative diseases.
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spelling pubmed-73149702020-07-02 Metformin Protects From Rotenone–Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis El-Ghaiesh, Sabah H. Bahr, Hoda I. Ibrahiem, Afaf T. Ghorab, Doaa Alomar, Suliman Y. Farag, Noha E. Zaitone, Sawsan A. Front Mol Neurosci Neuroscience Parkinson’s disease (PD) is a neurodegenerative disease that affects substantia nigra dopamine neurons. Many studies have documented the role of oxidative stress and angiogenesis in the pathogenesis of PD. Metformin (MTF) is an antidiabetic medication and AMP-activated protein kinase (AMPK) regulator that has shown antioxidant and antiangiogenic properties in many disorders. The aim of this study is to investigate the neuroprotective effect of MTF in a mouse model of rotenone-prompted PD with a highlight on its influence on the AMPK/forkhead box transcription factor O3 (FOXO3) pathway and striatal angiogenesis. In the running study, PD was induced in mice using repeated doses of rotenone and concomitantly treated with MTF 100 or 200 mg/kg/day for 18 days. Rotarod and pole tests were used to examine the animals’ motor functionality. After that, animals were sacrificed, and brains were isolated and processed for immunohistochemical investigations or biochemical analyses. Oxidant stress and angiogenic markers were measured, including reduced glutathione, malondialdehyde, the nuclear factor erythroid 2–related factor 2 (Nrf2), hemoxygenase-1, thioredoxin, AMPK, FOXO3, and vascular endothelial growth factor (VEGF). Results indicated that MTF improved animals’ motor function, improved striatal glutathione, Nrf2, hemoxygenase-1, and thioredoxin. Furthermore, MTF upregulated AMPK-FOXO3 proteins and reduced VEGF and cleaved caspase 3. MTF also increased the number of tyrosine hydroxylase (TH)–stained neurons in the substantia nigra neurons and in striatal neuronal terminals. This study is the first to highlight that the neuroprotective role of MTF is mediated through activation of AMPK-FOXO3 signaling and inhibition of the proangiogenic factor, VEGF. Further studies are warranted to confirm this mechanism in other models of PD and neurodegenerative diseases. Frontiers Media S.A. 2020-06-18 /pmc/articles/PMC7314970/ /pubmed/32625061 http://dx.doi.org/10.3389/fnmol.2020.00084 Text en Copyright © 2020 El-Ghaiesh, Bahr, Ibrahiem, Ghorab, Alomar, Farag and Zaitone. http://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 Neuroscience
El-Ghaiesh, Sabah H.
Bahr, Hoda I.
Ibrahiem, Afaf T.
Ghorab, Doaa
Alomar, Suliman Y.
Farag, Noha E.
Zaitone, Sawsan A.
Metformin Protects From Rotenone–Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis
title Metformin Protects From Rotenone–Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis
title_full Metformin Protects From Rotenone–Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis
title_fullStr Metformin Protects From Rotenone–Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis
title_full_unstemmed Metformin Protects From Rotenone–Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis
title_short Metformin Protects From Rotenone–Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis
title_sort metformin protects from rotenone–induced nigrostriatal neuronal death in adult mice by activating ampk-foxo3 signaling and mitigation of angiogenesis
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314970/
https://www.ncbi.nlm.nih.gov/pubmed/32625061
http://dx.doi.org/10.3389/fnmol.2020.00084
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