基于脑-肠轴探讨SGLT-2抑制剂通过改善脑卒中神经修复的机制OA

Objective To investigate the neuroprotective effects and underlying mechanisms of dapagliflozin(DAP)in a rat model of ischemic stroke(IS)induced by middle cerebral artery occlusion(MCAO).Methods The MCAO model was established and rats were randomly assigned to the sham,model,and DAP groups(n=10).DAP(1 mg/kg·d)was administered by gavage 2 h after reperfusion for 7 consecutive days.N eurological function was assessed using the modified neurological severity score(mNSS).Infarct volume,brain water content,and hippocampal neuronal apoptosis were measured.Gut microbiota composition was analyzed by 16S rRNA sequencing.Serum levels of NGF,BDNF,D-lactate,DAO,and inflammatory cytokines were determined by ELISA.Protein expression of ZO-1,Occludin,Claudin-1,cleaved Caspase-3,HMGB1,RAGE,NF-κB,and p-NF-κB was detected by Western blot.Results Compared with the model group,DAP significantly reduced mNSS scores,(P<0.01)infarct volume,brain water content,and neuronal apoptosis(P<0.01).16S rRNA sequencing revealed increased abundances of Lactobacillus and Bifidobacterium,and decreased Enterobacter in the DAP group,which were significantly correlated with mNSS scores(P<0.001).DAP increased serum NGF and BDNF levels,while reducing D-lactate,DAO,and inflammatory cytokines(all P<0.01).Western blot showed that DAP upregulated ZO-1,Occludin,and Claudin-1,while downregulating cleaved Caspase-3,HMGB1,RAGE,NF-κB,and p-NF-κB(all P<0.01).Conclusion DAP can improve neurological function and brain injury in MCAO rats by inhibiting apoptosis and inflammation and regulating intestinal flora.