In vivo preconditioning with normobaric hyperoxia induces ischemic tolerance partly by triggering tumor necrosis factor-α converting enzyme/tumor necrosis factor-α/nuclear factor-κB

Recent studies suggest that intermittent and prolonged normobaric hyperoxia (HO) results in brain ischemic tolerance (BIT), reducing ischemic brain injury. We have attempted to determine the time course of HO-induced BIT, and to explore the putative roles of tumor necrosis factor-alpha (TNF-alpha) converting enzyme TACE), TNF-alpha, and nuclear factor-kappa B (NF-kappa B) activation in mediating this effect. Two core experimental protocols were applied to rats (experiments 1 [E1] and 2 [E2] respectively). E1 rodents comprised six subgroups, breathing room air (RA; O-2=21%), or 95% oxygen (1-10) for 4, 8, 16 h (4RA, 8RA, 16RA and 4HO, 8HO, 16HO respectively). E2 rodents were divided into subgroups, exposed to 95% inspired HO for 4 h/day for six consecutive days (intermittent hyperoxia, InHO) or for 24 continuous hours (prolonged hyperoxia, PrHO). Each of these had a control group exposed to 21% oxygen in the same chamber. Twenty-four hours after pretreatment, each group was randomly divided to receive 60 min right middle cerebral artery occlusion (MCAO-operated), sham-operation (without MCAO), or no operation (intact). After 24 h reperfusion, neurologic deficit score (NDS), brain water content, Evans Blue extravasation (as a marker of blood-brain barrier permeability), TACE expression, serum TNF-alpha, and phosphor-kappa B alpha levels were assessed in all animals, and infarct volume in the MCAO-operated subgroups. E1: Compared with the control (RA) group, infarct volume was reduced by 58.6% and 64.4% in 16 h and 24 In respectively. NDS and Evans Blue extravasation was also reduced in 16 In and 24 h. There was no statistical difference among 4 h and 8 h. E2: Preconditioning with prolonged and intermittent HO decreased NDS, infarct volume and upregulated TACE and increased phosphor-kappa B alpha and serum TNF-alpha level significantly. Although further studies are needed to clarify the mechanisms of brain ischernic tolerance, InHO and PrHO may partly exert their effects via triggering TACE/TNF-alpha/NF-kappa B. (c) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.