Ceramide and Its Interconvertible Metabolite Sphingosine Function as Indispensable Lipid Factors Involved in Survival and Dendritic Differentiation of Cerebellar Purkinje Cells

Abstract

Ceramide generated from sphingomyelin has emerged as a new but conserved type of biologically active lipid. We previously found that endogenous sphingolipids are required for the normal growth of cultured cerebellar Purkinje neurons and that sphingomyelin is present abundantly in the somatodendritic region of these cells. To gain further insight into a potential role of the sphingomyelin/ceramide pathway, we investigated the effects of depletion of sphingolipids on the phenotypic growth and survival of immature Purkinje cells and the ability of ceramide or other sphingolipids to antagonize these effects. Inhibition of ceramide synthesis by ISP-i, a specific inhibitor of serine palmitoyltransferase, decreased cellular levels of sphingolipids. This treatment resulted in a decrease in cell survival accompanied by an induction of apoptotic cell death and aberrant dendritic differentiation of Purkinje cells with no detectable changes in other cerebellar neurons. Cell-permeable ceramides, sphingosine, or sphingomyelin overcame these abnormalities more effectively than other sphingolipids when added simultaneously with ISP-i. Exposure to bacterial sphingomyelinase in turn enhanced cell survival and dendritic branching complexity of Purkinje cells at different optimal concentrations. Furthermore, cell-permeable ceramide acted synergistically with the neurotrophin family, which has been previously shown to support Purkinje cell survival. These observations suggest that ceramide is a requisite for the survival and the dendritic differentiation of Purkinje cells.

Ceramide-induced cell death/survival in murine osteoblasts

“…An intriguing observation from this study was that treatment of cultured osteoblasts with up to 10 K6 M of C 2 -ceramide promoted cell survival, whereas higher doses (O10 K5 M) induced apoptosis which was similar to that observed in neuronal cells (Furuya et al 1998). It is largely unknown how ceramide possesses multiple functions, although different metabolites of ceramide may lead to distinct effects.…”

Involvement of Ceramide in Ischemic Tolerance Induced by Preconditioning with Sublethal Oxygen-Glucose Deprivation in Primary Cultured Cortical Neurons of Rats

“…In general, low concentrations of ceramide were found to promote cell survival in the hippocampal, 29) cerebellar Purkinje 30) and sympathetic 31) neurons, whereas higher concentrations of ceramide were found to induce cell death in the hippocampal, 29) cortical 32) and mesencephalic 33) neurons. The studies that correlated ceramide with neurodegeneration were of higher levels of ceramide accumulation.…”

Inhibition of de novo ceramide synthesis upregulates phospholipase D and enhances myogenic differentiation

“…Increase in ceramide is reported to be involved in the differentiation of a range of cell types: myelocytic leukemia HL60 cells (Okazaki et al, 1990), EL4 thymoma cells (Mathias et al, 1993), cerebellar Purkinje cells (Furuya et al, 1998), U937 monoblastic leukemia cells (Ragg et al, 1998), etc. However, in view of the consequences of ceramide level manipulations, a negative, rather than positive, role of this messenger on myogenic differentiation can be inferred.…”