Protective effect of 5,6,7,8-Tetrahydroxyflavone on high altitude cerebral edema in rats.

High altitude cerebral edema (HACE) is a potentially life-threatening disease encountered at high altitudes. However, effective methods for HACE prophylaxis are limited. Convincing evidence confirms that oxidative stress induced by hypobaric hypoxia (HH) is one of the main factors that account for the development of HACE. 5,6,7,8-Tetrahydroxyflavone (THF), a flavone with four consecutive OH groups in ring A, exhibited excellent antioxidant activity in vitro and could attenuate HH induced injury in vivo. The aim of this study was to investigate the protective effect of THF against HACE and its underlying mechanisms. THF administration significantly suppressed HH induced oxidative stress by reducing the formation of hydrogen peroxide and malondialdehyde, by increasing the levels of glutathione and superoxide dismutase in brain tissue. Simultaneously, THF administration inhibited inflammatory responses by decreasing the levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 in serum and brain tissue. In addition, THF administration mitigated the energy metabolism disorder induced by HACE as evidenced by decreased levels of lactic acid, lactate dehydrogenase and pyruvate kinase as well as increased ATP levels and ATPase activities. Furthermore, THF administration decreased the expression of matrix metalloproteinase-9, aquaporin 4, hypoxia-inducible factor-1α and vascular endothelial growth factor, which attenuated blood-brain barrier (BBB) disruption and brain edema. Additionally, THF administration improved HACE induced cognitive dysfunction. These results show that THF is a promising agent in the prevention and treatment of HACE.