Desferroxamine infusion increases cerebral blood flow: a potential association with hypoxia-inducible factor-1

Abstract

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.

Figure 1. Cerebrovascular haemodynamic changes in response to 8 h of DFO compared with PLB infusion

●, DFO; ○, PLB. ABP, BFV and CVR (ABP/BFV) are all expressed as the absolute value of the variable minus the baseline value of that variable. Values are means ± S.E.M. *P ≤ 0.03, for DFO compared with PLB.

Figure 2. DFO-mediated HIF-1 activation as shown by serum LDH concentrations (top panel) and by HIF-1 protein concentration in PBMCs (bottom panel)

All points are expressed as the absolute value of the variable minus the baseline value of that variable. Values are means ± S.E.M. *P ≤ 0.02, for DFO compared with PLB.