Neuroprotection in ischemia-reperfusion injury: An antiinflammatory approach using a novel broad-spectrum chemokine inhibitor
Neuroprotection in ischemia-reperfusion injury: An antiinflammatory approach using a novel broad-spectrum chemokine inhibitor
复制标题
DOI：
10.1097/00004647-200106000-00006
复制
发表时间：
2001-06-01
影响因子：
6.3
通讯作者：
Menon, DK
中科院分区：
文献类型：
--
作者：
Beech, JS;Reckless, J;Menon, DK
脑缺血再灌注损伤与血管白细胞和内源性小胶质细胞病理贡献的炎症反应有关。信号趋化因子协调不同炎症细胞类型和受损组织之间的交流，导致细胞趋化和病变占领。几种旨在预防这种炎症反应的治疗方法已经在中风的实验模型中证明了神经保护作用，但迄今为止，很少有研究人员将趋化因子作为潜在的治疗靶点。在目前的研究中，作者研究了NR58-3.14.3，一种新型的广谱趋化因子功能抑制剂（CXC和CC型）在脑缺血再灌注损伤大鼠模型中的神经保护作用。采用纤维法对大鼠进行90min局灶性缺血，72h再灌注。通过连续磁共振成像测量病变体积，并每日评估神经功能。静脉注射NR58-3.14.3，先给药2 mg/kg，后给药0.5 mg/kg。72小时内不间断输注。72h时，用定量免疫荧光法分析脑白细胞浸润、肿瘤坏死因子- α (tnf - α)和白细胞介素-8 （IL-8）样细胞因子。NR58-3.14.3在大脑中动脉闭塞后24、48和72小时显著减少病变体积达50%，这与48小时的显著功能改善相关。在nr58 -3.14.3处理的大鼠中，病灶周围区域的浸润粒细胞和巨噬细胞数量减少，但核心缺血区域的炎症细胞数量未见明显差异。作者报告了缺血病变内细胞因子、tnf - α和il -8样细胞因子的表达增加，但nr58 -3.14.3治疗大鼠与对照组之间没有差异。虽然趋化因子具有促炎或抗炎作用，但这些数据表明，趋化因子上调和表达在缺血再灌注损伤中的总体作用对预后不利。
Cerebral ischemia-reperfusion injury is associated with a developing inflammatory response with pathologic contributions from vascular leukocytes and endogenous microglia. Signaling chemokines orchestrate the communication between the different inflammatory cell types and the damaged tissue leading to cellular chemotaxis and lesion occupation. Several therapies aimed at preventing this inflammatory response have demonstrated neuroprotective efficacy in experimental models of stroke, but to date, few investigators have used the chemokines as potential therapeutic targets. In the current study, the authors investigate the neuroprotective action of NR58-3.14.3, a novel broad-spectrum inhibitor of chemokine function (both CXC and CC types), in a rat model of cerebral ischemia-reperfusion injury. Rats were: subjected to 90 minutes of focal ischemia by the filament method followed by 72 hours of reperfusion. Both the lesion volume, measured by serial magnetic resonance imaging, and the neurologic function were assessed daily. Intravenous NR58-3.14.3 was administered, 2 mg/kg bolus followed by 0.5 mg/kg . hour constant infusion for the entire 72-hour period. At 72 hours, the cerebral leukocytic infiltrate, tumor necrosis factor-alpha (TNF-alpha), and interleukin-8 (IL-8)-like cytokines were analyzed by quantitative immuno-fluorescence. NR58-3.14.3 significantly reduced the lesion volume by up to 50% at 24, 48, and 72 hours post-middle cerebral artery occlusion, which was associated with a marked functional improvement to 48 hours. In NR58-3.14.3-treated rats, the number of infiltrating granulocytes and macrophages within perilesional regions were reduced, but there were no detectable differences in inflammatory cell numbers within core ischemic areas. The authors reported increased expression of the cytokines, TNF-alpha and IL-8-like cytokines within the ischemic lesion, but no differences between the NR58-3.14.3-treated rats and controls were reported. Although chemokines can have pro- or antiinflammatory action, these data suggest the overall effect of chemokine up-regulation and expression in ischemia-reperfusion injury is detrimental to outcome.