Objective To explore the main protective mechanism of icariin(ICA)on memory impairment induced by chronic hypoxic exposure in mice.Methods Forty 8-week-old male C57BL/6 mice were selected to establish an animal model simulating hypoxic environment exposure at an altitude of 6 000 m.Forty mice were randomly divided into normoxia group,normoxia+ICA group,hypoxia group,hypoxia+ICA group(10 mice in each group).After 28 d of exposure,Y-maze and novel object recognition tests were performed to evaluate the spatial memory function of mice.The degree of microglia activation and neuronal damage in the hippocampus of mice were observed by immunofluorescence staining.The expression of iNOS,IL-1β,TNF-α,Cxcl-1 and IL-4 in hippocampus were detected by qRT-PCR.The concentration of quinolinic acid,a metabolite of tryptophane-kynuridine pathway,was detected by quinolinic acid kit in hippocampus,and the mRNA expression of Ido1,Kmo,Haao,Kynu and Kyat3 in tryptophane-kynuridine pathway was detected by qRT-PCR.Results Compared with the normoxia group,Y-maze and novel object recognition tests revealed significant spatial memory impairment in mice of hypoxia group(P＜0.01).Immunofluorescence staining demonstrated increased microglia activation and neuronal damage in hypoxia group compared with those in normoxia group(P＜0.01).The concentration of quinolinic acid in hippocampus was higher in hypoxia group than that in normoxia group(P＜0.01).qRT-PCR analysis indicated significantly elevated expression of inflammation-related molecules in hippocampus of mice in hypoxia group(P＜0.01).For those functional molecules related to tryptophan-kynurenine metabolism,Ido1(P＜0.01),Kmo(P＜0.01)and Haao(P＜0.01)were notably increased,while Kynu(P＜0.01)and Kyat3(P＜0.01)were significantly decreased in hypoxia group compared with those in normoxia group.In comparison with hypoxia group,hypoxia+ICA group had an improvement in spatial memory ability(P＜0.05),a reduction in microglial activation and neuronal damage in hippocampus(P＜0.05),as well as a decrease in expressions of inflammation-related molecules(P＜0.01)and functional molecules involved in tryptophan-kynurenine metabolism(P＜0.01).Conclusion ICA can regulate tryptophan-kynurenine metabolism in microglia,inhibit the inflammatory activation of microglia and quinolinic acid production,thereby alleviating hippocampal neuronal damage induced by chronic hypoxia and improving memory function in mice.
维普
万方数据