Antioxidants attenuate reperfusion injury after global brain ischemia through inhibiting nuclear factor-kappa B activity in rats.

Acta Pharmacol Sin 2003 Nov;24(11):1125-30

Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou 221002, China.

Aim: To investigate the effects of two antioxidants on the alterations of nuclear factor kappaB (NF-kappaB) activity and p65, p50 protein expression and phosphorylation of IkappaBalpha in rat hippocampus following global brain ischemia.

Methods: Using a 4-vessel occlusion (4-VO) as brain ischemia model, NF-kappaB protein (p65 or p50 subunit) expression was examined by Western blot analysis, and NF-kappaB activity was assayed by electrophoretic mobility shift assay (EMSA), and neuronal loss was observed by histology.

Results: NF-kappaB activity displayed a time-dependent manner, and p65, p50 proteins showed their peak levels after ischemia/reperfusion 6 h. NF-kappaB inductions (p65: 4.79+/-0.78, p50: 5.50+/-0.33, sham control=1) and activity (4.93+/-0.95) after 6 h of reperfusion were markedly reduced by pretreatment with antioxidants pyrrolidine dithiocarbamate (PDTC, 200 mg/kg) (p65: 1.11+/-0.74, p50: 1.38+/-0.98, activity: 2.20+/-0.86, respectively) or N-acetylcysteine (NAC, 300 mg/kg) (p65: 0.64+/-0.39, p50: 1.89+/-0.87, activity: 0.61+/-0.65), and histological observations of the pyramidal layer of CA1 also showed a reduction of neuronal loss in rat hippocampus (70 %+/-5 % or 92 %+/-4 % cells are survival, respectively). Furthermore, PDTC and NAC prevented the decrease (from 0.50+/-0.10 to 0.80+/-0.20 or 1.20+/-0.24, respectively) and phosphorylation (from 2.00+/-0.15 to 0.46+/-0.10 or 0.41+/-0.10, respectively) of IkappaBalpha protein in the cytoplasm.

Conclusion: The protective effects of antioxidants against ischemia/reperfusion-induced injury may be mediated by down-regulation of NF-kappaB activity. NF-kappaB activation and deactivation are controlled mainly through phosphorylation and degradation of IkappaBalpha following brain ischemia.

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November 2003
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