Proteasome inhibitor PS519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia
Proteasome inhibitor PS519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia
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DOI：
10.1161/01.str.31.7.1686
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发表时间：
2000-07-01
期刊：
影响因子：
8.3
通讯作者：
Tortella, FC
中科院分区：
文献类型：
--
作者：
Phillips, JB;Williams, AJ;Tortella, FC
背景和目的-脑缺血后再灌注脑损伤与梗死部位炎症反应的发展有关。蛋白酶体抑制剂阻断核因子-κ B活化，并在几种外周炎症动物模型中提供抗炎作用。我们测试了新的蛋白酶体抑制剂PS519在大鼠模型中的短暂局灶性脑缺血建立其作为一种神经保护治疗和相关的影响白细胞infiltration. Methods大鼠的药效学进行了2小时的局灶性脑缺血的细丝方法大脑中动脉闭塞（MCAo）。再灌注22或70小时后，测量梗死面积，并定量神经功能、脑电图（EEG）活动和/或中性粒细胞和巨噬细胞浸润。在MCAo后2小时以单次静脉推注给予PS519。此外，PS519的治疗窗口估计延迟治疗4或6小时后MCAo.Results-Dose-response分析梗死体积在24小时显示，PS519神经保护接近60%，临床评价显示神经功能和EEG活动的显着改善。在24小时时，在PSS 519处理的大鼠的皮质和纹状体梗塞组织中的神经元浸润也显著减少。将PS519处理延迟至4小时继续导致显著的神经保护。在72小时损伤模型中，PS519使梗死减少了40%，并且再次测量到神经功能和EEG恢复的显著改善。中性粒细胞和巨噬细胞浸润的相当大的减少是显而易见的。结论PS519减轻梗死和改善脑损伤大鼠的神经功能恢复，在一定程度上由减少白细胞炎症反应的影响。
Background and Purpose-Reperfusion brain injury after cerebral ischemia is associated with a developing inflammatory response at the site of infarction. Proteasome inhibitors block nuclear factor-kappa B activation and provide antiinflammatory effects in several animal models of peripheral inflammation. We tested the novel proteasome inhibitor PS519 in a rat model of transient focal ischemia to establish its pharmacodynamics as a neuroprotection treatment and related effects on leukocyte infiltration.Methods-Rats were subjected to 2 hours of focal cerebral ischemia by means of the filament method of middle cerebral artery occlusion (MCAo). After either 22 or 70 hours of reperfusion, infarct size was measured and neurological function, electroencephalographic (EEG) activity, and/or neutrophil and macrophage infiltration was quantified. PS519 was administered in a single intravenous bolus at 2 hours after MCAo. In addition, the therapeutic window for PS519 was estimated by delaying treatment for 4 or 6 hours after MCAo.Results-Dose-response analysis of infarct volume at 24 hours revealed that PS519 neuroprotection approached 60%, and clinical evaluations showed significant improvements in neurological function and EEG activity. Neutrophil infiltration at 24 hours was also significantly decreased in cortical and striatal infarcted tissue of PSS519-treated rats. Delaying the PS519 treatment up to 4 hours continued to result in significant neuroprotection. In the 72-hour injury model, infarction was reduced 40% by PS519, and significant improvements in neurological function and EEG recovery were again measured. Considerable reductions in both neutrophil and macrophage infiltration were evident.Conclusions-PS519 mitigates infarction and improves neurological recovery in brain-injured rats, an effect in part caused by a reduction in the leukocyte inflammatory response.