title: Ethanol triggers sphingosine 1-phosphate elevation along with neuroapoptosis in the developing mouse brain.
abstract: Our previous studies have indicated that de novo ceramide synthesis plays a critical role in ethanol-induced apoptotic neurodegeneration in the 7-day-old mouse brain. In this study, we examined whether the formation of sphingosine 1-phosphate (S1P), a ceramide metabolite, is associated with this apoptotic pathway. Analyses of basal levels of S1P-related compounds indicated that S1P, sphingosine, sphingosine kinase 2, and S1P receptor 1 increased significantly during postnatal brain development. In the 7-day-old mouse brain, sphingosine kinase 2 was localized mainly in neurons. Subcellular fractionation studies of the brain homogenates showed that sphingosine kinase 2 was enriched in the plasma membrane and the synaptic membrane/synaptic vesicle fractions, but not in the nuclear and mitochondrial/lysosomal fractions. Ethanol exposure in 7-day-old mice induced sphingosine kinase 2 activation and increased the brain level of S1P transiently 2-4 h after exposure, followed by caspase 3 activation that peaked around 8 h after exposure. Treatment with dimethylsphingosine, an inhibitor of sphingosine kinases, attenuated the ethanol-induced caspase 3 activation and the subsequent neurodegeneration. These results indicate that ethanol activates sphingosine kinase 2, leading to a transient increase in S1P, which may be involved in neuroapoptotic action of ethanol in the developing brain.
authors.affiliation: Division of Neurochemisty, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
authors.forename: Goutam
authors.initials: G
authors.lastname: Chakraborty
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Saito
authors.forename: Relish
authors.initials: R
authors.lastname: Shah
authors.forename: Rui-Fen
authors.initials: RF
authors.lastname: Mao
authors.forename: Csaba
authors.initials: C
authors.lastname: Vadasz
authors.forename: Mariko
authors.initials: M
authors.lastname: Saito
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000633:toxicity*; D000431:Ethanol / Q000633:toxicity*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate