Establishment of an experimental rat model of high altitude cerebral edema by hypobaric hypoxia combined with temperature fluctuation.

High altitude cerebral edema (HACE) is a kind of life threat disease encountered at high altitude, but the precise pathogenesis of it is far more understood. Hypobaic hypoxia (HH) and cold are conditions characteristic of high altitude environment. HH is always considered as the central causative factor for the development of HACE, but the effect of cold stress on HACE has been rarely investigated. The purpose of this study was to investigate the potential role of cold stress in the development of HACE and establish a stable experimental animal model. Male SPF Wistar rats were randomly divided into five groups for this experiment, control group (altitude, 1400 m, temperature, 25 ℃), NC + 2 ℃ group (altitude, 1400 m, temperature, 2 ℃), HH group (altitude, 6000 m, temperature, 25 ℃), HH+2 ℃ group (altitude, 6000 m, temperature, 2 ℃) and HH + 12/2 ℃ (altitude, 6000 m, temperature, 12 ℃/2 ℃ light/dark cycle). After exposure for 72 h, the blood and brain tissues were collected. Brain water content (BWC) and Evans Blue dye extravasation were used to assess the brain edema and blood-brain barrier (BBB) permeability, respectively. The levels of pro-inflammatory cytokines in serum were assessed via enzyme-linked immunosorbent assay. Oxidative stress markers and ATPase activity were determined using commercial kits. Western blotting was used to detect the expression of related proteins. Compared to control, HH+2 ℃ could significantly increase the BWC and BBB permeability, and these changes were further exacerbated by HH + 12/2 ℃. Furthermore, HH+2 ℃ and HH + 12/2 ℃ markedly increased the levels of H2O2 and MDA, restrained SOD and GSH levels and decreased Na+/K+-ATPase activitie compared with the control group. In addition, HH+2 ℃ and HH + 12/2 ℃ enhanced the levels of pro-inflammatory cytokines IL-1β, TNF-α and IL-6 in serum and significantly increased the expression of VEGF in brain compared with the control group, but only HH + 12/2 ℃ could increase the expression of AQP4. However, compared with control group, no significant differences in these parameters were observed in HH and NC+2 ℃groups. These results demonstrated that HH or cold stress alone did not successfully induce brain damage, while HH+2 ℃ could induce the onset of HACE via provoking injury caused by HH. HH + 12/2 ℃ was more obvious and efficient. Collectively, we firstly suggest that cold stress may promote the formation of HACE by aggravating the brain injury induced by HH exposure and supply an effective and reliable experimental rat model of HACE via HH combined with temperature fluctuation.