title: In vivo influence of ceramide accumulation induced by treatment with a glucosylceramide synthase inhibitor on ischemic neuronal cell death.
abstract: It has been shown that exogenous ceramide induces delayed neuronal death (DND) of cultured hippocampal neurons. To evaluate the role of endogenous ceramide in ischemic DND, the glucosylceramide synthase inhibitor, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), was used to generate ceramide in gerbil hippocampi in vivo. The trimethylsilylated derivatives of ceramide were analyzed directly by gas chromatography mass spectrometry, after separation with high-performance thin-layer chromatography. The ceramide compositions in vehicle hippocampus consisted mainly of C18:0 fatty acyl sphingosine (87.9%), with C16:0 and C20:0 ceramides being minor components (7.1% and 5.1%, respectively). Ceramide level in the hippocampi from gerbils subjected to D-PDMP treatment was 1.5-fold higher than those from vehicle-treated gerbils. In spite of the accumulation of ceramide observed in the D-PDMP group, the histological studies did not reveal any ischemic neuronal death in hippocampal CA1 neurons with the gerbils that had been subjected to a sham operation (2-min sublethal ischemia). These results suggest that the ceramide accumulation induced by blocking the de novo synthesis of glucosylceramide with D-PDMP may be independent of the metabolic pathway underlying ischemic DND.
authors.affiliation: Department of Biochemistry, Teikyo University, School of Medicine, Tokyo, Japan.
authors.forename: Harumi
authors.initials: H
authors.lastname: Hisaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimasaki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ueta
authors.forename: Masaru
authors.initials: M
authors.lastname: Kubota
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakane
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Nakagomi
authors.forename: Akira
authors.initials: A
authors.lastname: Tamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Masuda
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005849:Gerbillinae; D005963:Glucosylceramides / Q000096:biosynthesis; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D013110:Sphingosine / Q000378:metabolism
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D009025:Morpholines; C033110:RV 538; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D013110:Sphingosine