Off Target therapeutic effects of commonly used drugs to treat acute mountain sickness

Abstract

IntroductionAcute mountain sickness is a syndrome that effects ~60% of individuals ascending to high altitude, yet the etiology is still unclear. It has been proposed that reactive oxygen species (ROS) formed from acute high altitude exposure contribute to brain vascular leak and development of AMS. NF‐E2‐related factor 2 (Nrf2) is a transcription factor that regulates expression of greater than 90% of antioxidant genes.HypothesisWe postulated that some drugs currently used to treat AMS symptoms could induce Nrf2 activation and that by increasing anti‐oxidant status would decrease vascular damage from oxidative stress in hypoxic conditions.MethodsA MCF7 cell line stably transfected with a luciferase gene driven by an antioxidant response element, the known Nrf2 promoter, was used to screen. Drugs that showed favorable Nrf2 activation were further tested in brain microvascular endothelial cells to determine if they attenuated hypoxia induced ROS production and permeability. Finally, compounds were tested for their ability to induce Nrf2 and decrease brain leak (measured by Evans blue dye) in male Spraque Dawly rats exposed to high altitude (48 h, 19,000 ft).ResultsOf 9 drugs tested, Nifedipine and Methazolamide showed strong NRF2 activation. Cells in hypoxic conditions increased hydrogen peroxide production by two fold from normoxic. Pre‐treatment with Methazolamide, Nifedipine, and Protandim decreased ROS production back to normoxic concentrations. This response was blocked by siRNA against Nrf2. Resistance was decreased after 24 hr hypoxic exposure, which was restored to normoxic values with pre‐treatments of Protandim, Methazolamide, and Nifedipine. Only drugs that showed Nrf2 activation in‐vitro, decreased brain vascular leak, in‐vivo.ConclusionNrf2 activators are effective at reducing brain vascular leak from acute high altitude exposures.