The Role And Mechanism Of Calcium Binding Protein S100B In Central Nervous System Injury Induced By Gp120

BACKGROUND AND PURPOSENeurotoxicity induced by human immunodeficiency Virus-1(HIV-1)evelope protein gp120 is the main factor leading to pathogenesis of HIV-related neurocognitive disorder(HAND).Although Antiretroviral Therapy(ART)is widely used,infection of advanced brain injury 1s still a critical issue in prevention and treatment of AIDS.S100B protein is calcium binding protein belong to S100 protein family,which has a wide range of biological properties and is enriched in glial cells in central nervous system.The protein also has a certain regulatory effect on neurons while extracellular S100B has nutritional effect on neurons at low concentrations but it is neurotoxic at high concentrations,which regarded as a molecular marker of nerve damage commonly.Studies have shown that HIV-1 gp120 protein damage to central nervous system in the process of S100B participation.The purpose of this research is to find out the role of S100B in neurological injury of HIV-1 gp120 and its mechanism,meanwhile to provide basis for prevention and treatment of AIDS encephalopathy caused by HIV-1 infection.METHODS AND RESMLTSIn this research,U251 and sh-sy5y cells were used to construct in vitro models,and eight months gp120 transgenic C57BL/6 mice were used as an in vivo model for HAND study,compared to wildtype(WT)C57BL/6 mice,they were divided into three groups,control group,gp 120 group and S100B inhibitor group.1、The secretion of S100B protein in U251 cells was detected using ELISA.Gp120 protein treatment showed changes in the secretion of S100B in a time/dose-dependent manner.WB experiments demonstrated that the secretion of S100B was associated with RAGE expression changes.2、U251/neurons co-culture model was constructed and used for apoptosis and neuronal integrity detection assays.Results showed that gp120 protein stimulation of S100B could cause neuronal damage,ELISA results demonstrated that levels of inflammatory factors IL-6 and TNF-α were increased.3、Establishing dose/time-effect relationship of S100B inhibitors.Using the same method,we found that S100B inhibitors in the above co-culture model could protect neurons from injury and lower the level of inflammation.4.、Through immunohistochemical and immune imprinting analysis,it was shown that S100B expression in gp120 Tg mice and WT mice was correlated with changes in nerve inflammation and the degree of brain injury.5.、Compared with gp 120 group,decreased S100OB exression,nerve inflammation and brain injury degree were observed in drug treatment group(inhibitor SBi4211).These changes were associated with the reduction of RAGE.CONCLUSION1、Gp120 protein could induce the proliferation of astrocytes and enhance the expression of S100B,along with damage of neuronal cells;2、The S100B inhibitor SBi4211 could block the gp120-stimulated secretion of S100B and protect neurons from injury;3、SBi4211 could reduce the expression of S100B in mice and the level of nerve inflammation,meanwhile slow down the process of brain injury in gp120 transgenic mice.It might be associated with the reducing expression of receptor RAGE.