Earlier Pahan et al (Pahan oxidation markers have been identified in white matter tissue of MS patients, along with perturbations in glutamate homeostasis, which correlate with disease severity (Gilgun-Sherki et al., 2004, Smith et al., 1999). targets. Sphingomyelin, a major component of myelin membrane created by mature oligodendrocytes, is usually abundant in the CNS and ceramide, its main catabolic product released by activation of either AZD8186 neutral or acidic sphingomyelinase, serves as a potential lipid second messenger or mediator molecule modulating diverse cellular signaling pathways. Similarly, under certain conditions, sphingosine produced from ceramide by ceramidase is usually phosphorylated by sphingosine kinases to sphingosine-1 phosphate, another potent second messenger molecule. Both ceramide and sphingosine-1 phosphate regulate life and death of many cell types including brain cells and participate in pathogenic processes of MS. In this review, we have made an honest attempt to compile recent findings made by others and us relating to the role of sphingolipids in the disease process of MS. mice that carry non-functional Fas and spontaneously develop autoimmune disease (Dittel, 2000). Within seconds of Fas engagement by ligand or agonistic antibody, ASMase translocates from an intracellular pool and hydrolyze sphingomyelin to release ceramide that facilitates Fas clustering and recruitment of Fas-associated death domain (FADD) followed by procaspase 8. The association of FADD with procaspase 8 initiates a proteolytic cascade leading to cell death (Cremesti in the mouse cortex. Earlier Pahan et al (Pahan oxidation markers have been recognized in white matter tissue of MS patients, along with perturbations in glutamate homeostasis, which correlate with disease severity (Gilgun-Sherki et al., 2004, Smith et al., 1999). However, molecular mechanisms that couple oxidative stress to the loss of oligodendrocytes were poorly understood. We have recently exhibited the importance of NSMaseCceramide pathway in mediating oxidative stress-induced apoptosis and cell death of human main oligodendrocytes. We have found that numerous oxidative stress-inducing brokers, such as, superoxide radical produced by hypoxanthine and xanthine oxidase, hydrogen peroxide, aminotriazole capable of inhibiting catalase and increasing intracellular level of H2O2, or reduced glutathione-depleting diamide induce the activation of NSMase and the production of AZD8186 ceramide in human oligodendrocytes (Jana & Pahan, 2007). It is interesting to note that antisense knockdown of neutral, but not acidic, sphingomyelinase ablates oxidative stress-induced apoptosis and cell death in oligodendrocytes. BackCet al (Back et al., 1998) have also reported that oligodendrocytes are vulnerable to glutathione depletion caused by cystine deprivation, buthionine sulfoximine and diethylmaleate. Moreover, increases in the concentration of extracellular glutamate lead to a sustained activation of oligodendrocyte AMPA/kainate receptors resulting in the production of higher levels of ROS and apoptosis of oligodendrocytes (Benarroch, 2009). All these evidences suggest that oxidative stress and increased ceramide concentration via NSMase activation may represent an important component in the loss of oligodendrocytes in MS. Intracellular transmission transduction pathways activated by sphingolipids in MS Role of P75 NTR The discovery that neurotrophins bind to p75NTR and activate SM hydrolysis with subsequent ceramide elevation (Fig. 1) highlights the importance of ceramide in the regulation of survival and death signaling pathways in the CNS. Recent studies around the pathogenesis of MS white matter plaques have revealed upregulated p75NTR messenger RNA and protein in oligodendrocytes from MS plaques, but not in control white matter (Dowling em et al. /em , 1999). More interestingly, CNPase and p75NTR immunoreactivity co-localize with TUNEL staining indicating that the majority of dying cells were p75NTR expressing oligodendrocytes. Further, the observations that nerve growth factor (NGF) levels are elevated in the CSF of MS patients (Laudiero em et al. /em , 1992) and that MS lesions contain ILK both apoptotic oligodendrocytes and immature oligodendrocytes with increased p75NTR expression (Ozawa em et al. /em , 1994, Dowling et al., 1999) raise the possibility that p75NTR may play AZD8186 a role in the pathogenesis of MS. In addition, retroviral expression of Trk A in mature oligodendrocytes prevents NGF-induced p75NTR-dependent apoptosis further reinforcing p75NTR-induced ceramide elevation in this death signaling pathway AZD8186 (Yoon em et al. /em , 1998). Role.