title: Methamphetamine accelerates cellular senescence through stimulation of de novo ceramide biosynthesis.
abstract: Methamphetamine is a highly addictive psychostimulant that causes profound damage to the brain and other body organs. Post mortem studies of human tissues have linked the use of this drug to diseases associated with aging, such as coronary atherosclerosis and pulmonary fibrosis, but the molecular mechanism underlying these findings remains unknown. Here we used functional lipidomics and transcriptomics experiments to study abnormalities in lipid metabolism in select regions of the brain and, to a greater extent, peripheral organs and tissues of rats that self-administered methamphetamine. Experiments in various cellular models (primary mouse fibroblasts and myotubes) allowed us to investigate the molecular mechanisms of systemic inflammation and cellular aging related to methamphetamine abuse. We report now that methamphetamine accelerates cellular senescence and activates transcription of genes involved in cell-cycle control and inflammation by stimulating production of the sphingolipid messenger ceramide. This pathogenic cascade is triggered by reactive oxygen species, likely generated through methamphetamine metabolism via cytochrome P450, and involves the recruitment of nuclear factor-κB (NF-κB) to induce expression of enzymes in the de novo pathway of ceramide biosynthesis. Inhibitors of NF-κB signaling and ceramide formation prevent methamphetamine-induced senescence and systemic inflammation in rats self-administering the drug, attenuating their health deterioration. The results suggest new therapeutic strategies to reduce the adverse consequences of methamphetamine abuse and improve effectiveness of abstinence treatments.
authors: Department of Pharmacology, University of California Irvine, Irvine, California, United States of America.
authors: Giuseppe
authors: G
authors: Astarita
authors: Department of Pharmacology, University of California Irvine, Irvine, California, United States of America.
authors: Agnesa
authors: A
authors: Avanesian
authors: Drug Discovery and Development, Italian Institute of Technology, Genoa, Italy.
authors: Benedetto
authors: B
authors: Grimaldi
authors: Drug Discovery and Development, Italian Institute of Technology, Genoa, Italy.
authors: Natalia
authors: N
authors: Realini
authors: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, United States of America; Departement of Psychiatry, MPRC, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors: Zuzana
authors: Z
authors: Justinova
authors: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, United States of America.
authors: Leight V
authors: LV
authors: Panlilio
authors: Drug Discovery and Development, Italian Institute of Technology, Genoa, Italy.
authors: Abdul
authors: A
authors: Basit
authors: Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, National Institute on Drug Abuse, Baltimore, Maryland, United States of America.
authors: Steven R
authors: SR
authors: Goldberg
authors: Drug Discovery and Development, Italian Institute of Technology, Genoa, Italy; Department of Anatomy and Neurobiology, University of California Irvine, Irvine, California, United States of America.
authors: Daniele
authors: D
authors: Piomelli
mesh_terms: D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000633:toxicity*; D002518:Ceramides / Q000096:biosynthesis* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D012646:Self Administration; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D002518:Ceramides; D016328:NF-kappa B; D008694:Methamphetamine; D003577:Cytochrome P-450 Enzyme System