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Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation

BACKGROUND: Sudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation. METHODS AN...

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Autores principales: Zhu, Juan, Liu, Kewei, Huang, Kaibin, Gu, Yong, Hu, Yafang, Pan, Suyue, Ji, Zhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220525/
https://www.ncbi.nlm.nih.gov/pubmed/29895585
http://dx.doi.org/10.1161/JAHA.117.008389
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author Zhu, Juan
Liu, Kewei
Huang, Kaibin
Gu, Yong
Hu, Yafang
Pan, Suyue
Ji, Zhong
author_facet Zhu, Juan
Liu, Kewei
Huang, Kaibin
Gu, Yong
Hu, Yafang
Pan, Suyue
Ji, Zhong
author_sort Zhu, Juan
collection PubMed
description BACKGROUND: Sudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation. METHODS AND RESULTS: Rats were subjected to 9‐minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP‐activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation. Our results showed that metformin pretreatment elevated the 7‐day survival rate from 55% to 85% and significantly reduced neurologic deficit scores. Moreover, metformin ameliorated CA‐induced neuronal degeneration and glial activation in the hippocampal CA1 region, which was accompanied by augmented AMPK phosphorylation and autophagy activation in affected neuronal tissue. Inhibition of AMPK or autophagy with pharmacological inhibitors abolished metformin‐afforded neuroprotection, and augmented autophagy induction by metformin treatment appeared downstream of AMPK activation. CONCLUSIONS: Taken together, our data demonstrate, for the first time, that metformin confers neuroprotection against ischemic brain injury after CA/cardiopulmonary resuscitation by augmenting AMPK‐dependent autophagy activation.
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spelling pubmed-62205252018-11-15 Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation Zhu, Juan Liu, Kewei Huang, Kaibin Gu, Yong Hu, Yafang Pan, Suyue Ji, Zhong J Am Heart Assoc Original Research BACKGROUND: Sudden cardiac arrest (CA) often results in severe injury to the brain, and neuroprotection after CA has proved to be difficult to achieve. Herein, we sought to investigate the effects of metformin pretreatment on brain injury secondary to CA and cardiopulmonary resuscitation. METHODS AND RESULTS: Rats were subjected to 9‐minute asphyxial CA after receiving daily metformin treatment for 2 weeks. Survival rate, neurologic deficit scores, neuronal loss, AMP‐activated protein kinase (AMPK), and autophagy activation were assessed at indicated time points within the first 7 days after return of spontaneous circulation. Our results showed that metformin pretreatment elevated the 7‐day survival rate from 55% to 85% and significantly reduced neurologic deficit scores. Moreover, metformin ameliorated CA‐induced neuronal degeneration and glial activation in the hippocampal CA1 region, which was accompanied by augmented AMPK phosphorylation and autophagy activation in affected neuronal tissue. Inhibition of AMPK or autophagy with pharmacological inhibitors abolished metformin‐afforded neuroprotection, and augmented autophagy induction by metformin treatment appeared downstream of AMPK activation. CONCLUSIONS: Taken together, our data demonstrate, for the first time, that metformin confers neuroprotection against ischemic brain injury after CA/cardiopulmonary resuscitation by augmenting AMPK‐dependent autophagy activation. John Wiley and Sons Inc. 2018-06-12 /pmc/articles/PMC6220525/ /pubmed/29895585 http://dx.doi.org/10.1161/JAHA.117.008389 Text en © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
Zhu, Juan
Liu, Kewei
Huang, Kaibin
Gu, Yong
Hu, Yafang
Pan, Suyue
Ji, Zhong
Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation
title Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation
title_full Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation
title_fullStr Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation
title_full_unstemmed Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation
title_short Metformin Improves Neurologic Outcome Via AMP‐Activated Protein Kinase–Mediated Autophagy Activation in a Rat Model of Cardiac Arrest and Resuscitation
title_sort metformin improves neurologic outcome via amp‐activated protein kinase–mediated autophagy activation in a rat model of cardiac arrest and resuscitation
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220525/
https://www.ncbi.nlm.nih.gov/pubmed/29895585
http://dx.doi.org/10.1161/JAHA.117.008389
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