Neurons and Oligodendrocytes Recycle Sphingosine 1-Phosphate to Ceramide: SIGNIFICANCE FOR APOPTOSIS AND MULTIPLE SCLEROSIS*

摘要

Both cultured neonatal rat hippocampal neurons and differentiated oligodendrocytes rapidly metabolized exogenous C2- and C6-ceramides to sphingosine (Sph) and sphingosine 1-phosphate (S1P) but only minimally to C16–24-ceramides. Dihydrosphinolipids were unaffected but were increased by exogenous C6-dihydroceramide. Conversely, quantitative liquid chromatography-tandem mass spectrometry technology showed that exogenous S1P (0.25–10 μm) was rapidly metabolized to both Sph (a >200-fold increase) and predominantly C18-ceramide (a >2-fold increase). Longer treatments with either C2-ceramide (>2.5 μm) or S1P (10 μm) led to apoptotic cell death. Thus, there is an active sphingolipid salvage pathway in both neurons and oligodendrocytes. Staurosporine-induced cell death was shown to be associated with decreased S1P and increased Sph and C16/18-ceramide levels. The physiological significance of this observation was confirmed by the analysis of affected white matter and plaques from brains of multiple sclerosis patients in which reduced S1P and increased Sph and C16/18-ceramides were observed.