Lapchak Paul A, Zivin Justin A
University of California San Diego, Department of Neuroscience, MTF 316, 9500 Gilman Dr, La Jolla, Calif 92093-0624, USA.
Stroke. 2003 Aug;34(8):2013-8. doi: 10.1161/01.STR.0000081223.74129.04. Epub 2003 Jul 10.
It has been proposed that antioxidants and spin-trap agents may be neuroprotective after acute ischemia stroke. Although the antioxidant ebselen is currently in clinical trials, little is known about the effectiveness of ebselen, which has glutathione peroxidase-like and anti-inflammatory properties in embolic stroke models. Therefore, we determined the effects of ebselen when administered alone or with the thrombolytic tissue plasminogen activator (tPA), the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke.
Male New Zealand White rabbits were embolized by injection of a suspension of small blood clots into the middle cerebral artery via a catheter. Five minutes after embolization, ebselen (10 to 50 mg/kg) was infused intravenously. Control rabbits received infusions of the vehicle required to solubilize ebselen. In additional rabbits, ebselen (20 mg/kg) was administered 60 minutes after embolization, either alone or in combination with tPA (0.9 or 3.3 mg/kg tPA). Behavioral analysis was conducted 24 hours after embolization, allowing determination of the effective stroke dose (P50) or clot amount (mg) that produces neurological deficits in 50% of the rabbits.
A drug is considered neuroprotective if it significantly increases the P50 compared with the vehicle-treated control group. The P50 of controls 24 hours after embolization was 1.35+/-0.30 mg. Rabbits treated 5 minutes after embolization with 10, 20, or 50 mg/kg ebselen had P50 values of 2.12+/-0.56, 2.82+/-0.75 (P<0.05), and 0.49+/-0.54 mg, respectively. A significant neuroprotective effect was observed with the 20-mg/kg dose, but not if there was a 60-minute delay before administration (P50=1.69+/-0.32 mg). When tPA (3.3 mg/kg) was infused 60 minutes after embolization and ebselen (20 mg/kg) was injected at either 5 (P50=2.98+/-0.18 mg) or 60 (P50=3.60+/-0.79 mg) minutes, there was no additional neuroprotective effect compared with tPA alone (P50=3.38+/-0.55 mg). However, if ebselen (20 mg/kg) was administered concomitantly with low-dose tPA (0.9 mg/kg) 60 minutes after embolization, the P50 was 3.52+/-0.73 mg (P<0.05), indicating a synergistic effect of the drug combination because neither alone was effective (P50=1.69+/-0.32 and 1.54+/-0.36 mg, respectively).
This study indicates that ebselen may be neuroprotective when administered shortly after an embolic stroke, but the time- and dose-response analyses suggest that it has a narrow therapeutic window. Nevertheless, ebselen may be beneficial if administered concomitantly with a thrombolytic because it significantly enhanced the neuroprotective activity of low-dose tPA.
有人提出抗氧化剂和自旋捕获剂在急性缺血性卒中后可能具有神经保护作用。尽管抗氧化剂依布硒仑目前正在进行临床试验，但对于其在栓塞性卒中模型中具有谷胱甘肽过氧化物酶样和抗炎特性的有效性知之甚少。因此，我们确定了依布硒仑单独给药或与溶栓药物组织型纤溶酶原激活剂（tPA）联合使用时的效果，tPA是美国食品药品监督管理局批准的唯一用于治疗卒中的药物。
通过导管将小血凝块悬浮液注入雄性新西兰白兔的大脑中动脉，使其发生栓塞。栓塞后5分钟，静脉输注依布硒仑（10至50毫克/千克）。对照兔输注溶解依布硒仑所需的溶媒。在另外的兔中，栓塞后60分钟单独或与tPA（0.9或3.3毫克/千克tPA）联合给予依布硒仑（20毫克/千克）。栓塞后24小时进行行为分析，以确定在50%的兔中产生神经功能缺损的有效卒中剂量（P50）或血凝块量（毫克）。
如果一种药物与溶媒处理的对照组相比能显著提高P50，则认为该药物具有神经保护作用。栓塞后24小时对照组的P50为1.35±0.30毫克。栓塞后5分钟用10、20或50毫克/千克依布硒仑治疗的兔的P50值分别为2.12±0.56、2.82±0.75（P<0.05）和0.49±0.54毫克。观察到20毫克/千克剂量具有显著的神经保护作用，但如果给药前延迟60分钟则无此作用（P50=1.69±0.32毫克）。栓塞后60分钟输注tPA（3.3毫克/千克），并在5分钟（P50=2.98±0.18毫克）或60分钟（P50=3.60±0.79毫克）注射依布硒仑（20毫克/千克），与单独使用tPA（P50=3.38±0.55毫克）相比，没有额外的神经保护作用。然而，如果在栓塞后60分钟将依布硒仑（20毫克/千克）与低剂量tPA（0.9毫克/千克）同时给药，P50为3.52±0.73毫克（P<0.05），表明药物组合具有协同作用，因为单独使用时两者均无效（P50分别为1.69±0.32和1.54±0.36毫克）。
本研究表明，依布硒仑在栓塞性卒中后不久给药可能具有神经保护作用，但时间和剂量反应分析表明其治疗窗较窄。尽管如此，如果与溶栓药物同时给药，依布硒仑可能有益，因为它能显著增强低剂量tPA的神经保护活性。
