Effects of acute hypoxia and hyperthermia on the permeability of the blood-brain barrier in adult rats

1 Department of Radiology, ; 2 Experimental Imaging Centre, and ; 3 Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Alberta, Canada Submitted 14 November 2008 ; accepted in final form 27 July 2009 Acute mountain sickness (AMS) develops within a few hours after arrival at high altitude and includes headache, anorexia, nausea, vomiting, and malaise. This afflicts 15–25% of the general tourist population at moderate altitudes. High-altitude cerebral edema (HACE) is considered to be the end stage of severe AMS and has been suggested to be a vasogenic edema, raising the possibility that acute hypoxia may increase blood-brain barrier (BBB) permeability. At present, there are no good small-animal models to study this syndrome. We hypothesize 1 ) that acute hypoxia can damage the BBB and 2 ) that rat can be used as a model to study hypoxia-induced changes in BBB permeability, especially if hypoxia-induced hypothermia could be minimized with high ambient temperature (HAT). Male Wistar rats were exposed to 1, 2, and 7 days of hypobaric hypoxia (equivalent to 0.5 atm), and changes in the temperature and BBB permeability were studied. The extravasation of endogenous immunoglobulin G, a large molecule, did not increase during room temperature hypoxia but did increase when hypoxia was combined with HAT. Hypoxia caused a significant increase in the leakage of sodium fluorescein (mol wt 376 Da). The expression of endothelial barrier antigen (EBA), a protein associated with the BBB, was reduced to 50% between 24 and 48 h after exposure to hypoxia, and the loss was exacerbated by HAT. The values almost returned to control levels by 7 days, showing adaptation to hypoxia. Hypoxic rats exhibited sodium fluorescein leakage mainly in focal areas in the brain parenchyma. In conclusion, it is possible to have transient BBB damage through exposure to acute hypoxia, and this damage is exacerbated by increasing body temperature to more of a normothermic value. hypoxia; blood-brain barrier; endothelial barrier antigen; high altitude Address for reprint requests and other correspondence: J. F. Dunn, Dept. of Radiology, Univ. of Calgary, 3330 Hospital Dr., N.W., Calgary, Alberta T2N 4N1, Canada (e-mail: dunnj{at}ucalgary.ca ).