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Ceramide metabolism analysis in a model of binge drinking reveals both neuroprotective and toxic effects of ethanol
Author(s) -
Bae Mihyun,
Bandaru Veera Venkata Ratnam,
Patel Neha,
Haughey Norman J.
Publication year - 2014
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12834
Subject(s) - ceramide , binge drinking , neuroprotection , metabolite , alcohol intoxication , ethanol , chemistry , metabolism , ethanol metabolism , lipid metabolism , pharmacology , ceramide synthase , biochemistry , endocrinology , medicine , alcohol , poison control , alcohol consumption , apoptosis , environmental health , injury prevention
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 (Et OH ) 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 Et OH 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. Et OH 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. Et OH 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 Et OH intoxication may evoke a ceramide phenotype that is neuroprotective, whereas Et OH withdrawal results in a metabolic shift that increases the production of potentially toxic ceramide species.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.