Effects Of Flurbiprofen Axetil Pretreatment On Global Cerebral Ischemia Reperfusion Injury In Rats

Objective:To investigate the effects of pretreatment with flurbiprofen on global cerebral ischemia-reperfusion (I/R) injury in rats and the mechanism involved.Methods:Eighty-four Adult male Sprague-Dawley rats weighing 200～350 g were randomly divided into four groups(n=21 each): groupⅠshame operation (group S); groupⅡplacebo + global cerebral ischemia-reperfusion model group (group I/R); groupⅢflurbiprofen 5 mg/kg + global cerebral ischemia-reperfusion model group (groupF 5) and groupⅣflurbiprofen 10 mg/kg + global cerebral ischemia-reperfusion model group (group F10).Global cerebral ischemia was induced by 20 min occlusion of bilateral common carotid arteries combined with hypotension (MAP maintained at 35-45 mm Hg).In group F5 and F10 flurbiprofen axetil 5 mg/kg + blank emulsion 0.5ml/kg and 10 mg/kg was injected iv at 15 min before ischemia respectively. The neurological deficit(NDS) was scored (0=normal,100=brain death) at 6(T1),24 (T2) and 72 h(T3) of reperfusion by the same observer. Blood samples were taken from left internal jugular vein. And then the animals were killed and brains removed for determination of serum concentrations of TNF-αand IL-1β(using radioimmunoassay), expression of nuclear factor-kappa B (NF-κB) mRNA and intercellular adhesion molecule-1 (ICAM-1) mRNA in hippocampus (by RT-PCR), Pathological changes in CA1 region of hippocampus was observed at T1, T2 and T3 of reperfusion by HE staining.,Radioimmunoassay technique was used to determine TXA2 and PGI2 content of the brain tissue at T1, T2 and T3 of reperfusion.Results:pretreatment with flurbiprofen axetil 5 mg/kg or flurbiprofen axetil 10 mg/kg significantly reduced histopathological injury in CA1 region of hippocampus, improved neurological deficit score( NDS), reduced TXA2 content and TXA2/ PGI2 of the brain tissue.Moreover, the effect of reducing histopathological injury in CA1 region of hippocampus in group F10 is better than group F5. Compared with group S, NDS at T1-3 was significantly increased, expression of NF-κB mRNA and ICAM-1 mRNA at T1-3 was up-regulated and serum concentrations of TNF-αat T1,2 and IL-1βat T1-3 were significantly increased in the other three groups,concentrations of TXB2 and TXB2/6-keto-PGF1αat T1-3 in group I/R,concentrations of TXB2 at T2-3 and TXB2/6-keto-PGF1αat T2 in group F5 were significantly increased (P<0.05 or 0.01).Compared with group I/R, NDS at T1-3 was significantly decreased, expression of NF-κB mRNA and ICAM-1 mRNA at T1-3 was down-regulated and serum concentrations of TNF-αat T1,2 and IL-1βat T1-3 were significantly decreased in group F5,F10 ,TXB2 at T1-3 and TXB2/6-keto-PGF1αat T3 in group F5,TXB2 and TXB2/6-keto-PGF1αat T1-3 in group F10 were significantly decreased (P<0.05 or 0.01). The expression of ICAM-1 mRNA at T2,3 was down-regulated and serum concentrations of IL-1βat T2 significantly decreased in group F10 compared with group F5, (P<0.05 or 0.01). The histologic damage was significantly slighter in group F5,F10 than in group I/R and in group F10 than in groupF5 .Conclusion:Pretreatment with flurbiprofen axetil can protect against global cerebral ischemia through inhibition of the inflammatory reaction in hippocampus and inhibition of TXA2 content and TXA2/ PGI2 of the brain tissue in a dose-dependent manner in rats.