Study On Effect Of Pannexin1 Channel On Demyelination Model Mouse

Multiple sclerosis(MS)is a chronic inflammatory demyelinating and neurodegenerative autoimmune disease of the central nervous system.MS typically affects young adults,with an onset between 20-40 years of age and with a long course.In most patients,irreversible impaired neurological function will eventually lead to sensory symptoms,visual loss,motor manifestations and cognitive impairment.That poses a major economic and psychological burden to the patient’s family,and socioeconomic burden to the public.The overall pathogenesis of MS is still unclear,although this disease is known to result from interplay of genetic susceptibility and environment risk factors,and causes demyelination,inflammation and neurodegenerative damage in central nervous system.Characteristically,the lesion sites of different patients differ,which explains the heterogeneous clinical manifestations and course of MS between different patients;and because of the remyelination mechanisms in the nervous system,the clinical relapse and chronic progression occurs.Disease-modifying treatment is currently the mainstream therapeutic methods,which targets immune system and impacts the immune networks,but usually imposes great burden on the immune system and may promotes toxic adverse drug reactions,furthermore,it’s of little use for progressive MS.Therapies aimed at inhibiting demyelination and promoting remyelination can directly protect the demyelinating axons in MS disease and theoretically be useful for progressive MS.Therefore,it is of great significance to develop such therapeutic drugs or targets.In consideration of the complexity of MS,there are many kinds of animal model of MS used to study the distinct pathological process of MS.We established a precise cuprizone-induced demyelination mouse model through oral gavage to independently study the process of demyelination and remyelination.The copper chelator cuprizone(CPZ)can break copper homeostasis in mice and leads to metabolic stress in CNS cells,with selective toxicity for the most susceptible mature oligodendrocytes under suitable CPZ dosage,which eventually cause demyelination.Pannexin1(Panx1)channel is a widely expressed major transmembrane channel that release ATP and UTP,which plays an important role in many physiological activities like immune response,apoptosis.Besides that,it’s reported Panx1 participate in several pathological symptoms like neuropathic pain,inflammation,epilepsy,ischemia reperfusion injury,withdrawal symptoms.At present,there is no study on the role of Panx1 channel in demyelinating disease.Firstly,we examined the reliability and homogeneity of oral gavage CPZ model,and we found 400 mg/kg/d CPZ is the best dosage and adopted this dosage in later study.Then we established Panx1 blocked group by intraperitoneal injection of Panx1 channel blocker Carbenoxolone(CBX).It was found through behavior test,brain section staining and TEM that blocking Panx1 channel can’t reduce the behavioral deficiencies of MS model mice,but has a good protective effect on myelin sheath.We suspect that Panx1 channel promotes oligodendrocyte apoptosis in demyelinating mouse model,thus causing demyelination,but imposes no influence on the myelin function loss during demyelination.These studies provide new ideas and targets for MS treatment.