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Mechanism of ischemic tolerance induced by hyperbaric oxygen preconditioning involves upregulation of hypoxia-inducible factor-1 and erythropoietin in rats

¹Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai, People's Republic of China; and ²Departments of Neurosurgery and Physiology, Loma Linda University, Loma Linda, California

Submitted 22 March 2007 ; accepted in final form 17 December 2007

We studied the effect of hyperbaric oxygen (HBO) preconditioning on the molecular mechanisms of neuroprotection in a rat focal cerebral ischemic model. Seventy-two male Sprague-Dawley rats were pretreated with HBO (100% O₂, 2 atmospheres absolute, 1 h once every other day for 5 sessions) or with room air. In experiment 1, HBO-preconditioned rats and matched room air controls were subjected to focal cerebral ischemia or sham surgery. Postinjury motor parameters and infarction volumes of HBO-preconditioned rats were compared with those of controls. In experiment 2, HBO-preconditioned rats and matched room air controls were killed at different time points. Brain levels of hypoxia-inducible factor-1 (HIF-1) and its downstream target gene erythropoietin (EPO) analyzed by Western blotting and RT-PCR as well as HIF-1 DNA-binding and transcriptional activities were determined in the ipsilateral hemisphere. HBO induced a marked increase in the protein expressions of HIF-1 and EPO and the activity of HIF-1, as well as the expression of EPO mRNA. HBO preconditioning dramatically improved the neurobehavioral outcome at all time points (3.0 ± 2.1 vs. 5.6 ± 1.5 at 4 h, 5.0 ± 1.8 vs. 8.8 ± 1.4 at 8 h, 6.4 ± 1.8 vs. 9.7 ± 1.3 at 24 h; P < 0.01, respectively) and reduced infarction volumes (20.7 ± 4.5 vs. 12.5 ± 3.6%, 2,3,5-Triphenyltetrazolium chloride staining) after cerebral ischemia. This observation indicates that the neuroprotection induced by HBO preconditioning may be mediated by an upregulation of HIF-1 and its target gene EPO.

ischemic preconditioning; transcriptional factors; cerebral ischemia; brain injury; DNA-binding activity

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