Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal.

Autor:	Brynildsen JK; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Lee BG; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Perron IJ; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Jin S; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224., Kim SF; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224; skim132@jhmi.edu blendy@pennmedicine.upenn.edu.; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21224., Blendy JA; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; skim132@jhmi.edu blendy@pennmedicine.upenn.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Apr 17; Vol. 115 (16), pp. 4282-4287. Date of Electronic Publication: 2018 Apr 02.
DOI:	10.1073/pnas.1707047115
Abstrakt:	Cigarette smoking is the leading cause of preventable disease and death in the United States, with more persons dying from nicotine addiction than any other preventable cause of death. Even though smoking cessation incurs multiple health benefits, the abstinence rate remains low with current medications. Here we show that the AMP-activated protein kinase (AMPK) pathway in the hippocampus is activated following chronic nicotine use, an effect that is rapidly reversed by nicotine withdrawal. Increasing pAMPK levels and, consequently, downstream AMPK signaling pharmacologically attenuate anxiety-like behavior following nicotine withdrawal. We show that metformin, a known AMPK activator in the periphery, reduces withdrawal symptoms through a mechanism dependent on the presence of the AMPKα subunits within the hippocampus. This study provides evidence of a direct effect of AMPK modulation on nicotine withdrawal symptoms and suggests central AMPK activation as a therapeutic target for smoking cessation. Competing Interests: The authors declare no conflict of interest. (Copyright © 2018 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu