Jatana Manu, Giri Shailendra, Ansari Mubeen A, Elango Chinnasamy, Singh Avtar K, Singh Inderjit, Khan Mushfiquddin
Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
J Neuroinflammation. 2006 May 11;3:12. doi: 10.1186/1742-2094-3-12.
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.
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]-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-kappaB) and inflammatory inducible nitric oxide synthase (iNOS) were investigated both in vivo and in vitro.
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-kappaB 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-kappaB 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-kappaB from cytosol to nucleus.
The study demonstrates the neuroprotective potential of 5-LOX inhibition through down-regulation of NF-kappaB in a rat model of experimental stroke.
中风是全球主要的死亡原因之一，也是美国发病和死亡的主要原因。脑缺血再灌注（IR）引发一系列复杂的生化事件，包括炎症反应。源自5-脂氧合酶（5-LOX）的白三烯会引发炎症，因此参与了中风损伤的病理生物学过程。
为了在局灶性脑缺血再灌注大鼠模型中测试5-LOX抑制的神经保护效果，对缺血动物在缺血前或缺血后用强效选择性5-LOX抑制剂（N-[3-[3-（-氟苯氧基）苯基]-1-甲基-2-丙烯基]-N-羟基脲（BW-B 70C）进行治疗。在再灌注24小时后对它们进行脑梗死、神经功能缺损评分及5-LOX表达的评估。此外，还在体内和体外研究了BW-B 70C在调节核因子κB（NF-κB）和炎症诱导型一氧化氮合酶（iNOS）方面的机制和抗炎潜力。
BW-B 70C在缺血前和缺血后治疗均能减少梗死面积并改善神经功能缺损评分。对脑切片的免疫组织化学研究显示，缺血再灌注介导神经元和小胶质细胞中5-LOX表达增加。BW-B 70C通过阻止NF-κB激活下调5-LOX并抑制iNOS表达。另外两种结构不同的5-LOX抑制剂在缺血再灌注后也进行了给药：咖啡酸和2,3,5-三甲基-6-[12-羟基-5,10-十二碳二炔基]-1,4-苯醌（AA-861）。与BW-B 70C一样，它们也提供了显著的神经保护作用。此外，在体外，BW-B 70C抑制脂多糖（LPS）介导的BV2小胶质细胞系中一氧化氮生成、iNOS诱导及NF-κB激活。用BW-B 70C处理大鼠原代小胶质细胞证实可阻断LPS介导的NF-κB p65亚基从胞质溶胶向细胞核的转位。
该研究证明了在实验性中风大鼠模型中，通过下调NF-κB抑制5-LOX具有神经保护潜力。
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