Effects of deferoxamine-activated hypoxia-inducible factor-1 on the brainstem after subarachnoid hemorrhage in rats.

Abstract

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.

CONCLUSION:

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.

• Authors: Tomohito Hishikawa, Shigeki Ono, Tomoyuki Ogawa, Koji Tokunaga, Kenji Sugiu, Isao Date
• Journal: Neurosurgery (Neurosurgery) Vol. 62 Issue 1 Pg. 232-40; discussion 240-1 (Jan 2008) ISSN: 1524-4040 [Electronic] United States
• PMID: 18300912 (Publication Type: Journal Article)

Chemical References

• Hypoxia-Inducible Factor 1
• Deferoxamine

Topics

• Animals
• Brain Stem (drug effects, metabolism)
• Cerebrovascular Circulation (drug effects, physiology)
• Deferoxamine (pharmacology)
• Disease Models, Animal
• Electrophoretic Mobility Shift Assay (methods)
• Gene Expression Regulation (drug effects)
• Hypoxia-Inducible Factor 1 (metabolism)
• Male
• Rats
• Rats, Sprague-Dawley
• Subarachnoid Hemorrhage (pathology)