Mechanism of ischemic tolerance induced by hyperbaric oxygen preconditioning involves upregulation of hypoxia-inducible factor-1alpha and erythropoietin in rats.
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.
Gu
Guo-Jun
GJ
Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, People's Republic of China.
Li
Yun-Ping
YP
Peng
Zao-Yun
ZY
Xu
Jia-Jun
JJ
Kang
Zhi-Min
ZM
Xu
Wei-Gang
WG
Tao
Heng-Yi
HY
Ostrowski
Robert P
RP
Zhang
John H
JH
Sun
Xue-Jun
XJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002545:Brain Ischemia / Q000503:physiopathology / Q000628:therapy*; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000502:physiology; D004247:DNA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D005552:Forelimb / Q000502:physiology; D006931:Hyperbaric Oxygenation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D019194:Ischemic Preconditioning; D008297:Male; D018696:Neuroprotective Agents; D010100:Oxygen / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D004921:Erythropoietin; C009591:triphenyltetrazolium; D004247:DNA; D010100:Oxygen