Effect Of Platelet Activating Factor And Its Receptor-dependent And Receptor-independent Pathway In The Demyelination Of Central Nervous System

Background: Myelin sheath is a unique lipid-rich membranous structure in nervous system which concentrically wraps the axons and segmented by the Ranvier's node every 50-1000?m.Under the biological situation,the intact myelin sheath protects axons and induces the regeneration of injured axons.The particular component and structure of myelin not only allows the fast saltatory conduction of electrical impulses but also insulates the axons,which avoids the interferences between nearby axons.Demyelination is a pathological process characterized as the damage or the complete loss of myelin sheath on axons,which can be induced by several factors including inflammation,hypoxic ischemia,virus infection and autoimmune attack.The dysfunction of myelin can result in several symptoms such as muscle weakness,muscle stiffness and spasms,loss of coordination,vision loss,pain,and change in sensation.Demyelination has also been confirmed to be involved in various nervous system diseases such as multiple sclerosis,periventricular leukomalacia,neuromyelitis optica,optic neuritis,transverse myelitis,and acute disseminated encephalomyelitis.Despite the pathological characterization of demyelination diseases has been extensively discussed,the cellular and molecular mechanisms underlying the demyelination process are not yet well known.Platelet activating factor(PAF,1-alkyl-2-acetyl-snglycero-3-phosphocholine)is a potent endogenous phospholipid inflammatory mediator.Normal level of PAF can help maintain the biological activities,while the excess level of PAF has been found highly related to the development of various central nervous system demyelinating diseases.The treatments with PAF antagonists apparently attenuated the demyelination injuries in animal models,while no significance effect was found in clinical trials.Although PAF is widely accepted to exert its function by connecting to a unique G-protein coupled seven transmembrane receptor,emerging evidences demonstrated that PAF can still exert its potent functions even when PAFR was blocked or deleted,implying the existence of unknown PAFR-independent pathways.In the present study,we hypothesize that the up-regulation of PAF level enhances the demyelination in central nervous system,and this effect of PAF is not completely modulated by its receptor-dependent pathway.Results: 1.The deletion of PAF receptor down-regulated the endogenous expression of PAF acetyl hydrolase.2.The treatment of lysolecithin suppressed the expression of PAF acetyl hydrolase.3.During the development of central nervous system demyelination,excess level of PAF greatly enhance the demyelination injury,while the gene deletion of PAFR couldn't block this effect of PAF.4.PAF up-regulated IL-1? through receptor-dependent pathway.5.Through receptor-independent pathway,PAF up-regulated the TNF? and IL-6,as well as down-regulated the TGF-?1.6.In prenatal mouse cerebellum slices culture,the excess level of PAF activated the microglia through the receptor-independent pathway,while the astrocytes and oligodendrocytes were not apparently affected.Conclusion: By modulating several pro-inflammatory and anti-inflammatory factors,PAF enhanced the development of central nervous system demyelination.This effect of PAF is not completed rely on the PAF receptor-dependent pathway.