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

Abstract

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% O(2), 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-1alpha (HIF-1alpha) and its downstream target gene erythropoietin (EPO) analyzed by Western blotting and RT-PCR as well as HIF-1alpha DNA-binding and transcriptional activities were determined in the ipsilateral hemisphere. HBO induced a marked increase in the protein expressions of HIF-1alpha and EPO and the activity of HIF-1alpha, 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-1alpha and its target gene EPO.

The neuroprotective mechanism of brain ischemic preconditioning

“…In this IPC model, the activity of the antioxidant enzymes glutathione peroxidase, glutathione reductase, and Mn superoxide dismutase were significantly increased, whereas superoxide and hydrogen peroxide concentrations following OGD were significantly lower in the IPC group. Furthermore, cytochrome c release from mitochondria to the cytosol was suppressed in the ischemia tolerance-induced hippocampal CA1 region [65] Recent reports suggested that one mechanism of preconditioning probably involves hypoxia-inducible factor-1alpha (HIF1alpha) [66,67] . HIF-1alpha is a transcription factor that binds with a second protein (HIF-1beta) in the nucleus to promote elements in hypoxia-responsive target genes during hypoxia.…”

Response of Rat Erythrocyte Oxidative Stress Markers to Repetitive Hyperbaric Oxygen Exposures Up to 40 Daily Sessions / Odgovor Markera Oksidativnog Stresa U Eritrocitima Pacova Na Višestruko Izlaganje Hiperbaričnom Kiseoniku Do 40 Seansi Dnevno

“…Thus, the overall results prove the safety of long-term HBO treatments. More de tailed studies, including detections of the previously suggested molecules heme oxygenase-1 (25) and hypoxia inducible factor-a (37), warrant more precise knowledge in order to elucidate the underlying mechanisms of HBO-related oxidant/antioxidant interactions.…”

Restoring Vascular Function with Hyperbaric Oxygen Treatment: Recovery Mechanisms

“…Reduction of COX-2 expression by HBO 2 preconditioning provides protection in the rat model of transient global cerebral ischemia [106]. Gu et al [107] studied the effect of preconditioning on the molecular mechanisms of neuroprotection in a rat focal cerebral ischemic model. They found that ischemic tolerance induced by HBO 2 preconditioning involves upregulation of hypoxia-inducible factor-1alpha and erythropoietin in rats.…”

“…They found that ischemic tolerance induced by HBO 2 preconditioning involves upregulation of hypoxia-inducible factor-1alpha and erythropoietin in rats. This is interesting, since it resembles ischemic preconditioning where ischemic stimuli below the threshold of damage lead to ischemic tolerance [107], potentially suggesting that intermittent HBO 2 may represent signals perceived as a kind of pseudohypoxia. The decrease in the expression of the integrins LFA-1 and ICAM-1 is also a major mechanism for the protective effect of HBO 2 in ischemia-reperfusion injury [108].…”