Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion:: Effects of the PPAR-α agonist WY14643
Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion:: Effects of the PPAR-α agonist WY14643
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DOI：
10.1016/j.freeradbiomed.2006.04.030
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发表时间：
2006-08-15
影响因子：
7.4
通讯作者：
Fantozzi, Roberto
中科院分区：
文献类型：
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作者：
Collino, Massimo;Aragno, Manuela;Fantozzi, Roberto
本研究观察了选择性PPAR-α激动剂WY14643对大鼠海马区I/R损伤的影响。短暂性脑缺血(30min)后再灌流1~24 h，可显著增加脑组织中活性氧、一氧化氮(NO)和脂质过氧化终产物的生成，显著降低内源性抗氧化剂谷胱甘肽(GSH)水平。再灌注3~6h，血红素氧合酶-1(HO-1)、环氧合酶-2(COX-2)、诱导型一氧化氮合酶(INOS)和细胞间黏附分子-1(ICAM-1)蛋白表达增加。WY14643可抑制氧化应激及HO-1、iNOS和ICAM-1的表达，但对COX-2无明显影响。这些作用是由于抑制了p38丝裂原活化蛋白激酶和核因子-kappa B的激活。PPAR-α拮抗剂MK886取消了WY14643的有益作用。在中风试验中用于监测损伤的脑损伤标志物S100B蛋白在暴露于I/R的大鼠海马区水平很高，但WY14643显著降低。我们认为WY14643保护大脑免受过度氧化应激和炎症，因此可能对治疗中风有用。(C)2006 Elsevier Inc.保留所有权利。
This study investigated the effects of the selective peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist WY14643 on ischemia/reperfusion (I/R) injury in the rat hippocampus. Transient cerebral ischemia (30 min), followed by 1-24 h reperfusion, significantly increased the generation of reactive oxygen species, nitric oxide (NO), and lipid peroxidation end-products, as well as markedly reducing levels of the endogenous antioxidant glutathione. Reperfusion for 3-6 h led to increased expression of the proteins heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1). Pretreatment with WY14643 suppressed oxidative stress and expression of HO-1, iNOS, and ICAM-1, but bad no effect on COX-2. These effects are due to suppression of the activation of p38 mitogen-activated protein kinase and nuclear factor-kappa B. The PPAR-alpha antagonist MK886 abolished the beneficial effects of WY14643. The levels of S100B protein, a marker of cerebral injury used in stroke trials to monitor injury, were high in the hippocampus of rats exposed to I/R, but markedly reduced by WY14643. We propose that WY14643 protects the brain against excessive oxidative stress and inflammation and may thus be useful in treating stroke. (c) 2006 Elsevier Inc. All rights reserved.