HBEGF alleviates neuroinflammation, oxidative stress and blood-brain barrier disruption in high-altitude cerebral edema via activating the ErbB4/PI3K/AKT signaling.

BACKGROUND: This study investigated the regulation of HBEGF in high-altitude cerebral edema (HACE) and elucidated its underlying molecular mechanisms, with the goal of identifying a potential therapeutic target for this condition.

METHODS: Bioinformatics analysis was employed to assess HBEGF expression in acute mountain sickness, and the findings were further validated using a mouse model of HACE. The function of HBEGF in HACE mice was evaluated through a range of analytical techniques, including Morris water maze test, Evans blue staining, brain water content measurement, as well as histological staining, Western blot, dihydroethidium staining, immunofluorescence staining and ELISA of brains. The effect of HBEGF on the ErbB4/PI3K/AKT signaling was examined by Western blot. Rescue experiments were conducted to determine whether HBEGF regulates HACE through modulation of the ErbB4/PI3K/AKT signaling.

RESULTS: Bioinformatics analysis revealed reduced HBEGF expression in patients with acute mountain sickness, which was subsequently confirmed in brains of HACE mice. Overexpression of HBEGF improved the learning and memory abilities in HACE mice. It also promoted neuronal survival, alleviated neurological damage, blood-brain barrier (BBB) disruption, oxidative stress and inflammatory response, and inhibited microglial M1 polarization within brains of HACE mice. HBEGF activated the ErbB4/PI3K/AKT signaling within brains of HACE mice. The protective effects of HBEGF against HACE were abolished by treatment with ErbB4 inhibitor AST1306 and PI3K/AKT inhibitor LY294002.

CONCLUSION: HBEGF might represent a promising therapeutic target for HACE, which alleviated HACE through activating the ErbB4/PI3K/AKT signaling. Developing strategies to enhance HBEGF expression might offer a viable approach for the clinical HACE management.