The Empirical Study Of Cerebral HIF-1α Induced By Acetazolamide In The Amelioraton Of Acute Mountain Sickness: Evidence For Acidosis

Acetazolamide, a potent carbonic anhydrase inhibitor, has had a long history of effectiveness in prevention and treatment of acute mountain sickness (AMS). Traditionally, acetazolamide's efficacy has been attributed to metabolic acidosis, which is allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude. Hypoxia inducible factor (HIF) controls the transcription of genes involved in angiogenesis, erythropoiesis, glycolysis, and cell survival. HIF-1αlevels are a critical determinant of HIF activity. HIF-1αprotein level and HIF-1 DNA binding activities were increased in cerebral cortices and hippocampus of rats dosed with acetazolamide (100 mg/kg or 50 mg/kg, IP) for 5 days. Moreover, the mRNA levels of erythropoietin (Epo), glucose transporter-1 (Glut-1), vascular endothelial growth factor (Vegf), which are regulated by HIF-1, also increased. The normoxic induction of HIF-1αand HIF-1 mediated genes by acetazolamide might participate the mechanisms in which acetazolamide reduces symptoms of AMS. In further studies, cultured cortical neurons obtained from embryonic day 18 rats and PC12 cells were exposed to AP (pH 6.5) or SD (pH 7.2) media for 20 h under normoxia. The HIF-1αprotein level and activity of HIF-driven chloramphenicol acetyltransferase (CAT) reporters of cortical neurons and PC12 cells treated with acidosis media were significantly enhanced. The normoxic induction of HIF-1 activity by acidosis might play an important role in induction of the critical hypoxic regulatory factor HIF-1 by acetazolamide.