Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemiaReportar como inadecuado

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Journal of Neuroinflammation

, 3:12

First Online: 11 May 2006Received: 24 January 2006Accepted: 11 May 2006


BackgroundStroke is one of the leading causes of death worldwide and a major cause of morbidity and mortality in the United States of America. Brain ischemia-reperfusion IR triggers a complex series of biochemical events including inflammation. Leukotrienes derived from 5-lipoxygenase 5-LOX cause inflammation and are thus involved in the pathobiology of stroke injury.

MethodsTo test the neuroprotective efficacy of 5-LOX inhibition in a rat model of focal cerebral IR, ischemic animals were either pre- or post-treated with a potent selective 5-LOX inhibitor, N- 3-3-fluorophenoxy phenyl-1-methyl-2-propenyl-N-hydroxyurea BW-B 70C. They were evaluated at 24 h after reperfusion for brain infarction, neurological deficit score, and the expression of 5-LOX. Furthermore, the mechanism and the anti-inflammatory potential of BW-B 70C in the regulation of nuclear factor kappa B NF-κB and inflammatory inducible nitric oxide synthase iNOS were investigated both in vivo and in vitro.

Results and discussionBoth pre- and post-treatment with BW-B 70C reduced infarctions and improved neurological deficit scores. Immunohistochemical study of brain sections showed IR-mediated increased expression of 5-LOX in the neurons and microglia. BW-B 70C down-regulated 5-LOX and inhibited iNOS expression by preventing NF-κB activation. Two other structurally different 5-LOX inhibitors were also administered post IR: caffeic acid and 2, 3, 5-trimethyl-6- 12-hydroxy-5, 10-dodecadiynyl-1, 4-benzoquinone AA-861. As with BW-B 70C, they provided remarkable neuroprotection. Furthermore, in vitro, BW-B 70C inhibited lipopolysaccharide LPS mediated nitric oxide production, iNOS induction and NF-κB activation in the BV2 microglial cell line. Treating rat primary microglia with BW-B70C confirmed blockage of LPS-mediated translocation of the p65 subunit of NF-κB from cytosol to nucleus.

ConclusionThe study demonstrates the neuroprotective potential of 5-LOX inhibition through down-regulation of NF-κB in a rat model of experimental stroke.

Electronic supplementary materialThe online version of this article doi:10.1186-1742-2094-3-12 contains supplementary material, which is available to authorized users.

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Autor: Manu Jatana - Shailendra Giri - Mubeen A Ansari - Chinnasamy Elango - Avtar K Singh - Inderjit Singh - Mushfiquddin Khan


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