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.
Highlights
The abuse of methamphetamine (D-meth) is a major health concern in industrialized countries, where a socially diverse group of users seeks the drug for its desirable psychological and physiological effects—a combination of euphoria, heightened arousal, reduced appetite and decreased fatigue [1]
While conducting a survey of lipidomic abnormalities associated with self-administration of D-meth, we found that ceramide production is strongly increased in rats that voluntarily take the drug
In those organs, accrued ceramide biosynthesis was associated with activation of a senescence-like transcription program—characterized by enhanced expression of genes involved in cell-cycle control (e.g., p21, p16) and chronic inflammation (e.g., IL-6 and tumor necrosis factor-α (TNF-α))— which could be recapitulated in vitro by treating mouse fibroblasts or differentiated C2C12 myoblasts with D-meth
Summary
The abuse of methamphetamine (D-meth) is a major health concern in industrialized countries, where a socially diverse group of users seeks the drug for its desirable psychological and physiological effects—a combination of euphoria, heightened arousal, reduced appetite and decreased fatigue [1]. These neurochemical alterations can lead to long-lasting damage to the brain, especially in structures containing dopaminergic axon terminals, which contribute to the emotional and cognitive problems experienced by D-meth addicts [2,3,4] This transition to pathology has been attributed to a series of concurring events that include disruption of neuronal redox homeostasis [5,6,7,8], activation of apoptotic and necrotic processes [9], and recruitment of pro-inflammatory pathways dependent on the transcription nuclear factor NF-κB [7,10,11,12]. These results shed new light on the molecular mechanism underlying D-meth toxicity and identify potential therapeutic targets to attenuate the life-threatening consequences of D-meth exposure in recovering addicts
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