基于GRB2/ERK/CRLS1通路探讨益肺宣肺降浊方对血管性痴呆模型大鼠的改善作用机制OA

OBJECTIVE To explore the improvine mechanism of Yifei xuanfei jiangzhuo formula(YFXF)on vascular dementia(VAD)model rats based on the growth factor receptor-bound protein 2(GRB2)/extracellular signal-regulated kinase(ERK)/cardiolipin synthase 1(CRLS1)pathway.METHODS VAD rat model was established by permanent bilateral common carotid artery ligation.Forty-eight successfully modeled rats were randomly divided into the model group(normal saline),donepezil hydrochloride group(positive control group,0.2 g/kg),and YFXF low-and high-dose groups(12.18 and 24.36 g/kg,calculated based on the total amount of crude drug),respectively.In addition,a sham operation group(normal saline)was set up.There were 12 rats in each group.Daily intragastric administration of drug or normal saline was performed for 30 consecutive days.After the last administration,the spatial cognitive ability of the rats was evaluated,the pathological morphology of the hippocampus was observed,the contents of tumor necrosis factor-α(TNF-α)and interleukin-4(IL-4)in serum were detected,the expression levels of GRB2/ERK/CRLS1 pathway-related proteins and the mRNA levels of GRB2,CRLS1,NADH dehydrogenase subunit 1(ND1),Tafazzin(TAZ),phospholipid scramblase 3(PLSCR3)and the ATP content in hippocampal tissue were measured.RESULTS Compared with the sham operation group,the escape latency of rats in the model group was significantly prolonged(P＜0.05),and the number of crossing platform was significantly reduced(P＜0.05),while the number of pyramidal cells and Nissl bodies in the hippocampus decreased sharply;the content of TNF-α in serum was significantly increased(P＜0.05),and the content of IL-4 was significantly decreased(P＜0.05);the expression levels of GRB2 and CRLS1 proteins,the phosphorylation level of ERK protein,the relative expression levels of GRB2,CRLS1,ND1,TAZ,and PLSCR3 mRNA,and the content of ATP in hippocampal tissue were significantly decreased(P＜0.05).Compared with the model group,the above pathological changes in the hippocampal tissue of each administration group were alleviated,and the quantitative indicators were significantly restored(P＜0.05).CONCLUSIONS YFXF may improve hippocampal neuron injury in VAD rats by activating the GRB2/ERK/CRLS1 pathway,maintaining cardiolipin homeostasis,and improving mitochondrial energy metabolism.