Desferroxamine infusion increases cerebral blood flow: a potential association with hypoxia-inducible factor-1.
Finding an effective means to improve cerebral perfusion during hypoxic/ischaemic stress is essential for neuroprotection. Studies in animal models of stroke have shown that desferroxamine activates HIF-1 (hypoxia-inducible factor-1), reduces brain damage and promotes functional recovery. The present study was designed to investigate the effects of desferroxamine infusion on the cerebral circulation in humans. Fifteen volunteers were enrolled in a randomized double-blind placebo-controlled crossover study. We measured cerebral blood flow velocity by transcranial Doppler ultrasonography in the middle cerebral artery, arterial blood pressure, end-tidal CO(2), as well as HIF-1 protein and serum lactate dehydrogenase concentrations in response to 8 h of desferroxamine compared with placebo infusion. Cerebrovascular resistance was calculated from the ratio of steady-state beat-to-beat values for blood pressure to blood flow velocity. We found that desferroxamine infusion was associated with a significant cerebral vasodilation. Moreover, decreased cerebrovascular resistance was temporally correlated with an increased HIF-1 protein concentration as well as HIF-1 transcriptional activation, as measured by serum lactate dehydrogenase concentration. The findings of the present study provide preliminary data suggesting that activators of HIF-1, such as desferroxamine, may protect neurons against ischaemic injury by dilating cerebral vessels and enhancing cerebral perfusion.
Sorond
Farzaneh A
FA
Department of Neurology, Stroke Division, Brigham and Women's Hospital, Boston, MA 02115, USA. fsorond@partners.org
Shaffer
Michele L
ML
Kung
Andrew L
AL
Lipsitz
Lewis A
LA
D000328:Adult; D000368:Aged; D001783:Blood Flow Velocity; D001794:Blood Pressure / Q000502:physiology; D002560:Cerebrovascular Circulation; D018592:Cross-Over Studies; D003676:Deferoxamine / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017262:Siderophores / Q000494:pharmacology*; D018667:Tilt-Table Test; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*; D055815:Young Adult
D051793:Hypoxia-Inducible Factor 1; D018696:Neuroprotective Agents; D017262:Siderophores; D014665:Vasodilator Agents; D003676:Deferoxamine