Protective effect and mechanisms of Buyang Huanwu decoction against hypobaric hypoxia-induced brain injury in mice: involvement of inflammatory responses and HIF-1/PI3K-Akt-related pathways.

BACKGROUND/

OBJECTIVES

This study aimed to investigate the preventive and protective effect of Buyang Huanwu Decoction (BHD) against hypobaric hypoxia-induced brain injury in mice and to explore its underlying mechanisms. Particular emphasis was placed on evaluating whether BHD pretreatment could prevent or attenuate hypobaric hypoxia-induced neurological dysfunction and hippocampal injury, and on clarifying its potential mechanisms from the perspectives of inflammatory responses, metabolic regulation, and HIF-1/PI3K-Akt-related pathways.

METHODS

A mouse model of hypobaric hypoxia-induced brain injury was established by exposure to a simulated high-altitude hypoxic environment equivalent to an altitude of 6000 m for 72 h. Mice were assigned to the normal control, model, BHD-pretreated, and acetazolamide-positive control groups. BHD and acetazolamide were administered once daily by intragastric gavage, starting 4 days before hypobaric hypoxia exposure and continuing during the 72 h exposure period. Open field testing was performed to assess spontaneous locomotor activity and exploratory behavior. Hippocampal injury was evaluated by hematoxylin and eosin staining, Nissl staining, and HIF-1α immunofluorescence staining. Non-targeted serum metabolomics, network pharmacology, hippocampal transcriptomics, and RT-qPCR validation were integrated to explore the potential mechanisms of BHD pretreatment.

RESULTS

BHD pretreatment prevented hypobaric hypoxia-induced behavioral abnormalities and alleviated hippocampal pathological injury, neuronal loss, and Nissl body reduction. BHD also reduced excessive hippocampal HIF-1α expression. Multi-omics analyses suggested that the protective effect of BHD was associated with the regulation of inflammatory responses, metabolic disturbances, and HIF-1/PI3K-Akt-related signaling. RT-qPCR validation showed that BHD modulated the abnormal expression of HIF-1α, IL-6, VEGFA, NF-κB1, and STX1A in hippocampal tissue.

CONCLUSIONS

BHD exerts a preventive neuroprotective effect against hypobaric hypoxia-induced brain injury in mice. Its effects may involve coordinated regulation of hypoxic responses, inflammatory signaling, metabolic remodeling, and HIF-1/PI3K-Akt-related pathways.