Effects of preconditioning with normobaric hyperoxia on Na⁺/Ca²âº exchanger in the rat brain.

BACKGROUND: Recent studies suggest that normobaric hyperoxia (HO) reduces hypoxia-reoxygenation injury in the rat brain. We have attempted to determine the effect of HO on Na(+)-Ca(2+) exchangers (NCX) in the rat stroke model. METHODS: Rats were divided into two experimental groups. The first group was exposed to 95% inspired HO for 4h/day for 6 consecutive days (HO). The second group acted as the control, and was exposed to 21% oxygen in the same chamber. Each main group was subdivided to middle cerebral artery occlusion (MCAO-operated) and intact (without any surgery) subgroups. After 48 h from pretreatment, MCAO-operated subgroups were subjected to 60 min of right MCAO. After 24h reperfusion, neurologic deficit score (NDS) and infarct volume were measured in MCAO-operated subgroups. The NCXs expression levels of the core, penumbra and subcortical regions were assessed in sham-operated and intact subgroups. RESULT: Preconditioning with HO decreased NDS and infarct volume, and increased the expression of NCX1, NCX2 and NCX3 in the penumbra, NCX2, NCX3 in the core and NCX1 and NCX3 in the subcortex. CONCLUSION: Although further studies are needed to clarify the mechanisms of ischemic tolerance, HO partly is associated with the expression of NCX1, 2, 3 consistent with an active role in the genesis of ischemic protection.

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

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-kappaB (NF-kappaB) 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 (HO) 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- kappaBalpha 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 h respectively. NDS and Evans Blue extravasation was also reduced in 16 h 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-kappaBalpha and serum TNF-alpha level significantly. Although further studies are needed to clarify the mechanisms of brain ischemic tolerance, InHO and PrHO may partly exert their effects via triggering TACE/TNF-alpha/NF-kappaB.

3-Ethyl-sulfanyl-5-methyl-1-phenyl-7-(pyrrolidin-1-yl)-1H-pyrimido[4,5-e][1,3,4]thia-diazine.

In the crystal structure of the title compound, C(18)H(21)N(5)S(2), the thia-diazine six-membered ring and pyrrolidine five-membered ring display boat and envelope conformations, respectively. The crystal structure contains weak C-H⋯N and C-H⋯S hydrogen bonding.