title: Nrf2 activation: a potential strategy for the prevention of acute mountain sickness.
abstract: Reactive oxygen species (ROS) formed during acute high altitude exposure contribute to cerebral vascular leak and development of acute mountain sickness (AMS). Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) is a transcription factor that regulates expression of greater than 90% of antioxidant genes, but prophylactic treatment with Nrf2 activators has not yet been tested as an AMS therapy. We hypothesized that prophylactic activation of the antioxidant genome with Nrf2 activators would attenuate high-altitude-induced ROS formation and cerebral vascular leak and that some drugs currently used to treat AMS symptoms have an additional trait of Nrf2 activation. Drugs commonly used to treat AMS were screened with a luciferase reporter cell system for their effectiveness to activate Nrf2, as well as being tested for their ability to decrease high altitude cerebral vascular leak in vivo. Compounds that showed favorable results for Nrf2 activation from our screen and attenuated high altitude cerebral vascular leak in vivo were further tested in brain microvascular endothelial cells (BMECs) to determine if they attenuated hypoxia-induced ROS production and monolayer permeability. Of nine drugs tested, with the exception of dexamethasone, only drugs that showed the ability to activate Nrf2 (Protandim, methazolamide, nifedipine, amlodipine, ambrisentan, and sitaxentan) decreased high-altitude-induced cerebral vascular leak in vivo. In vitro, Nrf2 activation in BMECs before 24h hypoxia exposure attenuated hypoxic-induced hydrogen peroxide production and permeability. Prophylactic Nrf2 activation is effective at reducing brain vascular leak from acute high altitude exposures. Compared to acetazolamide, methazolamide may offer better protection against AMS. Nifedipine, in addition to its known vasodilatory activities in the lung and protection against high altitude pulmonary edema, may provide protection against brain vascular leak as well.
authors.affiliation: Division of Cardiology, Cardiovascular Pulmonary Research Group, School of Medicine, Aurora, CO 80045, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Lisk
authors.forename: Joe
authors.initials: J
authors.lastname: McCord
authors.forename: Swapan
authors.initials: S
authors.lastname: Bose
authors.forename: Tim
authors.initials: T
authors.lastname: Sullivan
authors.forename: Zoe
authors.initials: Z
authors.lastname: Loomis
authors.forename: Eva
authors.initials: E
authors.lastname: Nozik-Grayck
authors.forename: Thies
authors.initials: T
authors.lastname: Schroeder
authors.forename: Karyn
authors.initials: K
authors.lastname: Hamilton
authors.forename: David C
authors.initials: DC
authors.lastname: Irwin
mesh_terms: D000532:Altitude Sickness / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002531:Cerebellum / Q000098:blood supply / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents
keywords: Calcium channel blockers; Carbon anhydrase inhibitors; Cerebral; Endothelin receptor antagonist; Free radicals; High altitude sickness; Nrf2; Vascular leak