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

• Published in: Journal of the American Heart Association Vol. 7; no. 12
• Main Authors: Zhu, Juan, Liu, Kewei, Huang, Kaibin, Gu, Yong, Hu, Yafang, Pan, Suyue, Ji, Zhong
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 19.06.2018; Wiley
• Subjects: AMP-Activated Protein Kinases - metabolism; AMP‐activated protein kinase signal transduction; Animals; Apoptosis - drug effects; autophagy; Autophagy - drug effects; Brain Ischemia - enzymology; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Brain Ischemia - prevention & control; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - enzymology; CA1 Region, Hippocampal - physiopathology; CA1 Region, Hippocampal - ultrastructure; cardiac arrest; Cardiopulmonary Resuscitation - adverse effects; diabetic therapy/glitazones; Disease Models, Animal; Heart Arrest - enzymology; Heart Arrest - pathology; Heart Arrest - physiopathology; Heart Arrest - therapy; Male; metformin; Metformin - pharmacology; Neurons - drug effects; Neurons - enzymology; Neurons - ultrastructure; neuroprotection; Neuroprotective Agents - pharmacology; Original Research; Phosphorylation; Rats, Sprague-Dawley; Signal Transduction; metformin; autophagy; diabetic therapy/glitazones; AMP‐activated protein kinase signal transduction; cardiac arrest; neuroprotection
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/jaha.117.008389

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. 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. 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.