Insights into abnormal sphingolipid metabolism in multiple sclerosis: targeting ceramide biosynthesis as a unique therapeutic strategy

Multiple sclerosis (MS) is a fatal demyelinating disease that primarily affects axons leading to massive neurodegeneration. Many studies have reported the causes and drawn the conclusions that multiple factors such as recurrent viral infections, hereditary link, and environmental condition are involved in the pathogenesis of MS. In essence, all these reports indicate a severe change in the biochemical milieu in the central nervous system (CNS) leading to inflammation and neurodegeneration. Recent studies in our laboratory revealed aberrant sphingolipid metabolism and accumulation of toxic sphingosine in the CNS tissues in MS patients. An elevation in sphingosine in MS brain white matter and plaque indicated that sphingosine toxicity might mediate degeneration of oligodendrocytes contributing to demyelination. An intermittent increase in ceramide followed by sphingosine accumulation in spinal cords from Lewis rats with experimental autoimmune encephalitis (EAE) and also stimulation of serine-palmitoyltransferase (SPT) activity correlated with induction of apoptosis in the lumbar spinal cord in EAE animals. Cytokine-stimulated ceramide elevation in cultured human oligodendrocytes was almost completely blocked by myriocin, an inhibitor of SPT. Myriocin exposure also protected oligodendrocytes from induction of apoptosis. Sphingosine toxicity via ceramide biosynthesis contributed to oligodendrocyte degeneration in both EAE and MS. Although many clinical trials are being conducted for MS, to the best of our knowledge, there is still no sphingolipid-targeted therapy available. Hence, we propose that sphingosine toxicity via ceramide generation may be a potential therapeutic target in both EAE and MS.