Effects of deferoxamine-activated hypoxia-inducible factor-1 on the brainstem after subarachnoid hemorrhage in rats.
OBJECTIVE
Hypoxia-inducible factor (HIF)-1 is a transcription factor that regulates the expression of various neuroprotective genes. The goal of this study was to clarify the relationship between HIF-1 expression and subarachnoid hemorrhage (SAH) and to characterize the effects of deferoxamine (DFO)-induced increases in HIF-1 protein levels on the brainstem and the basilar artery (BA) after experimental SAH.


METHODS
Rat single- and double-hemorrhage models (injected on Days 0 and 2) of SAH were used. We assessed the time courses for HIF-1 protein levels in the brainstems and the BA diameters within 10 minutes and 6 hours on Days 1 and 2 in the single-SAH model, and also on Day 7 in the double-SAH model. After induction of double hemorrhage in rats, DFO was injected intraperitoneally. We then evaluated HIF-1 protein expression and brainstem activity, BA diameter, and brainstem blood flow.


RESULTS
After the rats experienced SAH, HIF-1 protein expression was significantly greater at 10 minutes in the single-injection model and at 7 days in the double-injection model than at similar time points in the control group, and these increases correlated with degrees of cerebral vasospasm. DFO injection resulted in significant increases in HIF-1 protein expression and activity in the brainstems of rats with SAH, compared with the rats with SAH that were given placebos, and the rats without SAH in the double-hemorrhage model. Cerebral vasospasm and reduction of brainstem blood flow were significantly attenuated in the rats that were administered DFO.


CONCLUSIONS
These results show that a DFO-induced increase in HIF-1 protein level and activity exerts significant attenuation of BA vasospasm and reduction of brainstem blood flow in the rat model of SAH. DFO may be a promising agent for treating clinical SAH.
Hishikawa
Tomohito
T
Department of Neurological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. thishi@hsp.ncvc.go.jp
Ono
Shigeki
S
Ogawa
Tomoyuki
T
Tokunaga
Koji
K
Sugiu
Kenji
K
Date
Isao
I
D000818:Animals; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D003676:Deferoxamine / Q000494:pharmacology*; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000473:pathology*
D051793:Hypoxia-Inducible Factor 1; D003676:Deferoxamine