Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia
<p>Abstract</p> <p>Background</p> <p>Stroke 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 inflammati...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2006-05-01
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| Series: | Journal of Neuroinflammation |
| Online Access: | http://www.jneuroinflammation.com/content/3/1/12 |
| _version_ | 1818386387001409536 |
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| author | Singh Inderjit Singh Avtar K Elango Chinnasamy Ansari Mubeen A Giri Shailendra Jatana Manu Khan Mushfiquddin |
| author_facet | Singh Inderjit Singh Avtar K Elango Chinnasamy Ansari Mubeen A Giri Shailendra Jatana Manu Khan Mushfiquddin |
| author_sort | Singh Inderjit |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Stroke 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.</p> <p>Methods</p> <p>To 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]-<it>N</it>-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 <it>in vivo </it>and <it>in vitro</it>.</p> <p>Results and discussion</p> <p>Both 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.</p> <p>Conclusion</p> <p>The study demonstrates the neuroprotective potential of 5-LOX inhibition through down-regulation of NF-κB in a rat model of experimental stroke.</p> |
| first_indexed | 2024-12-14T03:53:14Z |
| format | Article |
| id | doaj.art-c3461688c93d46f5bbd939d9f0b5a63b |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-14T03:53:14Z |
| publishDate | 2006-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-c3461688c93d46f5bbd939d9f0b5a63b2022-12-21T23:18:09ZengBMCJournal of Neuroinflammation1742-20942006-05-01311210.1186/1742-2094-3-12Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemiaSingh InderjitSingh Avtar KElango ChinnasamyAnsari Mubeen AGiri ShailendraJatana ManuKhan Mushfiquddin<p>Abstract</p> <p>Background</p> <p>Stroke 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.</p> <p>Methods</p> <p>To 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]-<it>N</it>-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 <it>in vivo </it>and <it>in vitro</it>.</p> <p>Results and discussion</p> <p>Both 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.</p> <p>Conclusion</p> <p>The study demonstrates the neuroprotective potential of 5-LOX inhibition through down-regulation of NF-κB in a rat model of experimental stroke.</p>http://www.jneuroinflammation.com/content/3/1/12 |
| spellingShingle | Singh Inderjit Singh Avtar K Elango Chinnasamy Ansari Mubeen A Giri Shailendra Jatana Manu Khan Mushfiquddin Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia Journal of Neuroinflammation |
| title | Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia |
| title_full | Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia |
| title_fullStr | Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia |
| title_full_unstemmed | Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia |
| title_short | Inhibition of NF-κB activation by 5-lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia |
| title_sort | inhibition of nf κb activation by 5 lipoxygenase inhibitors protects brain against injury in a rat model of focal cerebral ischemia |
| url | http://www.jneuroinflammation.com/content/3/1/12 |
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