Résumé
Objective The preventive effect of epigallocatechin gallate(EGCG)on hyperglycemia-induced hemorrhagic transformation(HT)was analyzed,and the underlying mechanisms were further explored.Methods Male SD rats were randomly divided into sham operation group(Sham,n = 20),model group(n = 27),hyperglycemia model group(HG,n = 43),and EGCG group(n = 43).In the model group,only the electrocoagulation cerebral ischemia model was established,and the HG group and the EGCG group were used to establish the HT model with acute hyperglycemia combined with electrocoagulation cerebral ischemia model.In addition,EGCG was adminis-tered by gavage for 5 days before cerebral ischemia at a dose of 50 mg/kg/d.Further studies confirmed the relevant targets by using network pharmacology to predict the potential targets and pathways of EGCG in the occurrence of HT.Results Compared with the model group,the mortality rate of the rats in the HG group was significantly increased[21.2%(6/27)vs.51.2%(22/43),P＜0.05].The mortality of rats in the EGCG group was significantly lower than that in the HG group[30.20%(13/43)vs.51.2%(22/43),P＜0.05].Second,mNSS,Longa score and infarct volume in the EGCG group were significantly lower than those in the HG group(P＜0.05).The incidence of HT in the HG group was higher than that in the model group(59.3%vs.90.7%).EGCG significantly reduced the incidence of hyperglycemia-induced HT to 69.8%.Compared with the HG group,EGCG decreased the hemoglobin content from(53.42±5.11)mg/dL to(37.04±2.39)mg/dL respectively(P＜0.05).Network pharmacology revealed that Nrf2-Keap1-mediated neuroinflammation may be associated with hyperglycemia-induced HT.The expression of Nrf2 and Keap1 was significantly decreased and the expression of TLR4 and phosphorylation of NF-κB was significantly increased in the HG group,but EGCG reversed this process.Conclusion EGCG pretreatment prevents the occurrence of HT,which may be related to the neuroprotection mediated by activation of the Nrf2-Keap1 signaling pathway.
Résumé
Objective To explore the role of protective function of Sestrin2(Sesn2)to mitochondria in alleviating cognitive dysfunction in mice with sepsis-associated encephalopathy(SAE).Methods 6-week-old male C57BL/6J mice were randomly divided into three groups:sham group,CLP group and CLP plus eupatilin group,40 mice in each group.A sepsis model was induced by cecal ligation and perforation(CLP).The CLP plus eupatilin group was treated with eupatilin.Neurobehavioral test and Morris water maze(MWM)were used to deter-mine neurobehavior and spatial learning and memory function in mice.The number of neurons in hippocampal CA1 area was counted by Nissl staining.HT22 cells were randomly divided into a control group(Con),lipopolysaccha-ride group(LPS),LPS plus eupatilin treatment group(LPS plus eupatilin)and LPS plus eupatilin and Nrf2 siRNA treatment group(LPS plus eupatilin and si-Nrf2).Apoptosis was analyzed by terminal deoxynucleotidyl transferase-mediated nick end labeling(TUNEL)staining,Mitochondrial membrane potential(MMP)was used to analyze mitochondrial damage.Results Seven days after CLP,as compared with sham mice,Sesn2 in hippocampus and cortex decreased significantly in CLP mice(P<0.01).As compared with CLP group,the survival rate in CLP plus eupatilin group increased significantly(P<0.05).As compared with sham group,the mice in CLP group showed a relatively high nerve injury score(P<0.05),and had fewer platform crossings and shorter target stay time,while the mice in CLP plus eupatilin group exhibited a lower injury score(P<0.05),and stayed in the target area for a longer time(P<0.05).As compared with sham group,the co-localization rate of neurons,Sesn2 and Nrf2 in CLP group decreased significantly(P<0.05),and the number of CD68/Iba-1 positive microglia increased significantly(P<0.05),while CLP plus eupatilin group reversed these changes.As compared with Con group,apoptosis and MMP level in LPS group increased significantly(P<0.01),while apoptosis and MMP level in LPS plus eupatilin group were lower than those in LPS group(P<0.05).However,Nrf2 knockdown(LPS plus eupatilin and si-Nrf2 group)reversed the anti-apoptosis and mitochondrial protection of eupatilin.Conclusions Eupatilin can alleviate cognitive dysfunction and neurological deficit in SAE mice by activating Sesn2-Nrf2 pathway,and improve inflammatory microenvironment by alleviating mitochondrial dysfunction.