Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke model
Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke model
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DOI：
10.1111/j.1600-079x.2004.00138.x
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发表时间：
2004-09-01
影响因子：
10.3
通讯作者：
Cheung, RTF
中科院分区：
文献类型：
--
作者：
Pei, Z;Cheung, RTF
脑缺血/再灌注后的炎症反应在缺血性脑损伤中起着关键的致病作用。一氧化氮(NO)、环氧合酶-2(COX-2)和髓过氧化物酶(MPO)是重要的炎症介质。神经元型一氧化氮合酶(NNOS)是缺血/再灌流过程中过量NO的主要来源。COX-2的诱导和表达MPO的中性粒细胞的浸润是迟发性炎症损伤的关键因素。此前，我们在大鼠大脑中动脉闭塞(MCAO)卒中模型中证明，在缺血前给予褪黑素可显著减少脑梗塞体积。在本研究中，我们观察了5 mg/kg褪黑素对成年雄性SD大鼠右侧MCAO后24、48和72小时nNOS、COX-2、MPO和胶质纤维酸性蛋白(GFAP)免疫反应性的影响。褪黑素对血流动力学参数无影响。与假手术组大鼠相比，缺血/再灌流导致同侧脑组织中nNOS和ir-GFAP阳性细胞数增加(各时间点相似)。缺血/再灌流后出现COX-2阳性反应细胞(24小时最强，72小时有再次升高趋势)或MPO阳性细胞(24小时最强)。单次注射褪黑素可显著减轻nNOS、COX-2或MPO阳性细胞同侧的增加，但不影响同侧ir-GFAP的改变。我们的结果表明，褪黑素治疗部分是通过抑制随后的炎症反应来介导对缺血/再灌注损伤的神经保护作用。
Inflammatory response following cerebral ischemia/reperfusion plays a key pathogenic role in ischemic cerebral damage. Nitric oxide (NO), cyclooxygenase-2 (COX-2) and myeloperoxidase (MPO) are important inflammatory mediators. Neuronal NO synthase (nNOS) is a major initial source of excessive NO during ischemia/reperfusion. Induction of COX-2 and infiltration of polymorphonuclear cells expressing MPO are critical factors in delayed inflammatory damage. Previously, we demonstrated that administration of melatonin before ischemia significantly reduced the infarct volume in a rat middle cerebral artery occlusion (MCAO) stroke model. In this study, we examined the effect of pretreatment with melatonin at 5 mg/kg on the immunoreactivity (ir) for nNOS, COX-2, MPO, and glial fibrillary acidic protein (GFAP) at 24, 48, and 72 hr after right-sided endovascular MCAO for 1 hr in adult male Sprague-Dawley rats. Melatonin did not affect the hemodynamic parameters. When compared with rats with sham MCAO, ischemia/reperfusion led to an ipsilateral increase in cells with positive ir for nNOS (similar at all times) and in ir-GFAP (similar at all times). Ischemia/reperfusion led to appearance of cells with positive ir for COX-2 (greatest at 24 hr with a tendency to increase again at 72 hr) or MPO (greatest at 24 hr). A single dose of melatonin significantly lessened the ipsilateral increase in cells with positive ir for nNOS, COX-2 or MPO, but did not influence the ipsilateral change in ir-GFAP. Our results suggest that melatonin treatment mediates neuroprotection against ischemia/reperfusion injury partly via inhibition of the consequential inflammatory response.