Preventing High Altitude Cerebral Edema in Rats with Repurposed Anti-Angiogenesis Pharmacotherapy.
BACKGROUND
High altitude cerebral edema (HACE) is a fulminant, deadly, and yet still unpredictable brain disease. A new prophylactic treatment for HACE and its predecessor, acute mountain sickness (AMS), needs to be developed without the contraindications or adverse effect profiles of acetazolamide and dexamethasone. Since neovascularization signals are likely key contributors to HACE/AMS, our approach was to examine already existing anti-angiogenic drugs to inhibit potential initiating HACE pathway(s). This approach can also reveal crucial early steps in the frequently debated mechanism of HACE/AMS pathogenesis.


METHODS
We exposed four rat cohorts to hypobaric hypoxia and one to sea level (hyperbaric) conditions. The cohorts were treated with saline controls, an anti-angiogenesis drug (motesanib), a pro-angiogenesis drug (deferoxamine), or an intraperitoneal version of the established AMS prophylaxis drug, acetazolamide (benzolamide). Brain tissue was analyzed for cerebrovascular leak using the Evans Blue Dye (EVBD) protocol.


RESULTS
We observed significantly increased EVBD in the altitude control and pro-angiogenesis (deferoxamine) cohorts, and significantly decreased EVBD in the anti-angiogenesis (motesanib), established treatment (benzolamide), and sea-level cohorts.


CONCLUSIONS
Anti-angiogenesis-treated cohorts demonstrated less cerebrovascular extravasation than the altitude control and pro-angiogenesis treated rats, suggesting promise as an alternative prophylactic HACE/AMS treatment. The leak exacerbation with pro-angiogenesis treatment and improvement with anti-angiogenesis treatment support the hypothesis of early neovascularization signals provoking HACE. We demonstrate statistically significant evidence to guide further investigation for VEGF- and HIF-inhibitors as HACE/AMS prophylaxis, and as elucidators of still unknown HACE pathogenesis.Tarshis S, Maltzahn J, Loomis Z, Irwin DC. Preventing high altitude cerebral edema in rats with repurposed anti-angiogenesis pharmacotherapy. Aerosp Med Hum Perform. 2016; 87(12):1031-1035.
Kendall Regional Medical Center of the Miami Emergency Department, University of Colorado School of Medicine, Aurora, CO, USA.
Samantha
S
Tarshis
Joanne
J
Maltzahn
Zoe
Z
Loomis
David C
DC
Irwin
D000086:Acetazolamide / Q000494:pharmacology; D000531:Altitude; D000532:Altitude Sickness / Q000517:prevention & control*; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001929:Brain Edema / Q000517:prevention & control*; D002199:Capillary Permeability / Q000187:drug effects*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects*; D002550:Cerebral Veins / Q000187:drug effects*; D003676:Deferoxamine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009841:Oligonucleotides; D051381:Rats; D017207:Rats, Sprague-Dawley
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D002257:Carbonic Anhydrase Inhibitors; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; C519562:imetelstat; D003676:Deferoxamine; D000086:Acetazolamide