Role of intermittent hypoxic training combined with methazolamide in the prevention of high-altitude cerebral edema in rats

Although intermittent hypoxia training (IHT) and methazolamide (MTZ) alone can prevent high-altitude cerebral edema (HACE) to varying degrees, their efficacy and dispersion remain limited. However, only a handful of trials have explored the effectiveness of the IHT and MTZ combination in preventing HACE. Rats were first exposed to hypobaric hypoxia (5000 m, 54.02 kPa, 10.8% fraction of inspired oxygen (FiO₂)) with simultaneous exhaustive exercise (EE) for different durations to determine the ideal condition for establishing a rat model of HACE. Rats receiving various courses of IHT were subjected to this condition, and changes in behaviour, brain water content (BWC), pathology and brain protein expression were evaluated. Meanwhile, rats received different doses of MTZ before and during hypoxia exposure with simultaneous EE. Finally, rats receiving the IHT and MTZ combination were then exposed to hypoxia with simultaneous EE. Systemic inflammation and mild cerebral edema developed in rats after 6 h of hypobaric hypoxia with simultaneous EE. Rats showed severe impairment of spatial and memory functions after 2 days of hypobaric hypoxia with simultaneous EE, and the pathology of their brain showed significant dilated perivascular spaces, cell swelling, vacuolar degeneration and reduced neuron count. BWC, serum inflammatory factors and expression of vascular endothelial growth factor (VEGF) and aquaporin 4 (AQP4) proteins in the hippocampus increased significantly. Both IHT and MTZ differentially counteracted hypobaric hypoxia-induced spatial and memory function impairments and increased BWC, pathological changes and expression of AQP4 and VEGF proteins in the hippocampus. Among these, the long-course IHT (BID, 14 d) combined with MTZ (200 mg/kg/d) showed the most significant improvement, restoring the rats' indices to normal levels. Continuous hypobaric hypoxia with simultaneous EE for 2 days resulted in significant HACE in rats, which may be used to establish a rat model of HACE. Both IHT and MTZ alleviated HACE in rats to varying degrees, among which long-course IHT (BID, 14 d) combined with MTZ (200 mg/kg/d) effectively prevented HACE in rats.