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Sphingolipids: Breaking the Blood Brain Barrier

Sphingolipids comprise a variety of lipids with sphingoid bases as the backbone. Based on their structural complexity, sphingolipids can be further classified as sphingoid bases (for example, sphingosine), ceramide (N-acylated sphingoid bases), phosphosphingolipids (containing phosphorous moiety as head group, for example, sphingomyelin and sphingosine 1-phosphate) and glycosphingolipids (ceramide with sugar residue(s) at the 1-hydroxyl position). Sphingolipids are a major component of the cell membrane and are believed to locate mostly on the outer leaflet, helping to form a stable and resistant outer leaflet to protect cells from harmful environmental factors. Sphingolipids also participate in the formation of lipid rafts and a myriad of signal transduction events. The involvement of sphingolipids in the pathophysiology of many common human diseases has rendered them as the target of drug development efforts in recent years. One sphingosine derivative, fingolimod (FTY720), has been approved by the FDA for treatment of multiple sclerosis. Recently, Dr. Ronald Cannon, from the National Institutes of Health in Research Triangle Park, NC, and colleagues demonstrated that sphingolipids improve drug delivery to the brain through inhibiting the activity of P-glycoprotein (Cannon et al, (2012) Proc Natl Acad Sci USA 190(39): 15930-5). Driven by ATP energy, P-glycoprotein is an efflux pump that blocks the crossing of small-molecule drugs through the blood-brain-barrier to enter the CNS. Several sphingolipid derivatives, sphingosine-1-phosphate (S1P), fingolimod (FTY720) and its active metabolite (FTY720 phosphate, FTY720P), all effectively reduced P-glycoprotein transport activity and increased the uptake of three radiolabeled drugs, (3)H-verapamil, (3)H-loperamide and (3)H-paclitaxel.

Enzo Life Sciences offers a comprehensive portfolio of sphingolipids, including ceramide, phosphosphingolipids and glycosphingolipids, providing important tools for studying membrane structures, lipid raft functions, signaling transductions, as well as drug mechanisms and discoveries.

 

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