Ceramide metabolism analysis in a model of binge drinking reveals both neuroprotective and toxic effects of ethanol

Authors

  • Mihyun Bae,

    1. Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Veera Venkata Ratnam Bandaru,

    1. Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Neha Patel,

    1. Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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  • Norman J. Haughey

    Corresponding author
    1. Richard T. Johnson Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    2. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    • Address correspondence and reprint requests to Norman J. Haughey, Department of Neurology, The Johns Hopkins University School of Medicine, Pathology 517, 600 North Wolfe Street, Baltimore, MD 21287, USA. E-mail: nhaughe1@jhmi.edu

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Abstract

Binge drinking is a common form of alcohol abuse that involves repeated rounds of intoxication followed by withdrawal. The episodic effects of binge drinking and withdrawal on brain resident cells are thought to contribute to neural remodeling and neurological damage. However, the molecular mechanisms for these neurodegenerative effects are not understood. Ethanol (EtOH) regulates the metabolism of ceramide, a highly bioactive lipid that is enriched in brain. We used a mouse model of binge drinking to determine the effects of EtOH intoxication and withdrawal on brain ceramide metabolism. Intoxication and acute alcohol withdrawal were each associated with distinct changes in ceramide regulatory genes and metabolic products. EtOH intoxication was accompanied by decreased concentrations of multiple ceramides, coincident with reductions in the expression of enzymes involved in the production of ceramides, and increased expression of ceramide-degrading enzymes. EtOH withdrawal was associated with specific increases in ceramide C16:0, C18:0, and C20:0 and increased expression of enzymes involved with ceramide production. These data suggest that EtOH intoxication may evoke a ceramide phenotype that is neuroprotective, whereas EtOH withdrawal results in a metabolic shift that increases the production of potentially toxic ceramide species.

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We used a mouse model of binge drinking – a common form of alcohol abuse – to directly compare the effects of ethanol (EtOH) during intoxication and acute withdrawal on brain ceramide metabolism. Gene and metabolite analysis suggest that intoxication is associated with a protective phenotype, as evidenced by reductions in several ceramides. By contrast, acute withdrawal was associated with a degenerative phenotype that was manifested by the elevations in several ceramide species. These data suggest that neural damage may occur during the acute EtOH withdrawal phase and may involve increased production of neurotoxic ceramide species. The image depicts primary metabolic pathways regulated during EtOH intoxication (green) and those most active during withdrawal (red). SMase, Sphingomyelin phosphodiesterase; SGMS, sphingomyelin synthase; CerS, ceramid synthase; S1P, sphingosine-1P; sphK, sphingosine kinase.

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