Tamoxifen as an effective neuroprotectant in an endovascular canine model of stroke
Tamoxifen as an effective neuroprotectant in an endovascular canine model of stroke
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DOI：
10.3171/2010.8.jns09352
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发表时间：
2011-04-01
影响因子：
4.1
通讯作者：
Drazin, Doniel
中科院分区：
文献类型：
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作者：
Boulos, Alan S.;Deshaies, Eric M.;Drazin, Doniel
对象。他莫昔芬在啮齿类动物中被证明是一种有效的抗中风神经保护剂。由于其他神经保护药物在人体试验中失败，因此有必要在大型动物模型中对他莫昔芬进行研究，以进一步评估该药物的有效性。在这项研究中，作者开发了一种犬前循环梗死的血管内模型来模拟人类的临床情况。他们评估了以下假设：1)他们将能够持续产生颈内动脉（ICA）末端梗死，2)他莫昔芬是一种有效的神经保护剂，可预防犬中风。24只雄性比格犬（体重9-11 kg），切除双侧股动脉，分别选择性置管椎动脉和左ICA。在透视引导下，经椎动脉置入微导管，引导导管进入基底动脉、后交通动脉、ICA终端：终端注入1 ml凝块，阻断大脑中动脉（MCA）和大脑前动脉（ACA）起源。在前12只犬中，血管造影证实了闭塞。采用犬卒中评分（CSS）（评分范围0-18[0 =检查时完好，18 =昏迷）]。然后将这些动物杀死，并用2,3,5-三苯四氮氯化铵（TTC）对它们的大脑进行染色。随后的12只狗进行了一项盲法随机研究，作者比较了血栓注射后1小时静脉注射他莫昔芬（5mg /kg）和等体积的载体（二甲亚砜）的结果。3小时后，动物接受磁共振成像，拔管，并进行临床检查。血凝块注射后8小时处死，采用TTC染色。在第一组中，梗死面积和css与血管造影血管的闭塞程度一致。与ACA和MCA闭塞相比，ACA、MCA和大脑后动脉闭塞导致更大的梗死和更高的卒中评分。在第二组中，他莫昔芬显著降低了梗死面积并改善了临床结果。在他莫昔芬治疗的动物中，平均梗死面积减少40% (p < 0.05)，平均CSS显著低于药物治疗的动物（p < 0.001）。MR成像测定体积、ttc测定体积与神经学临床预后有显著相关性（p < 0.05）。使用这种血管内中风模型，作者能够持续地在犬科动物中产生梗死，其范围与人类颈动脉末梢闭塞相似。此外，血管造影可以预测随后的临床病程和梗死面积。他莫昔芬在显著改善犬神经功能缺损和减少中风的大小方面是有效的。这项研究迈出了第一步，证明了一种有前途的人类神经保护剂在大型动物身上的有效性。(DOI: 10.3171 / 2010.8.jns09352)
Object. Tamoxifen has been shown to be a potent neuroprotectant against stroke in rodents. Because other neuroprotectant medications have failed in human trials, a study of tamoxifen in a large-animal model was necessary to further assess the drug's effectiveness. For this study, the authors developed an endovascular model of anterior circulation infarction in canines to mimic the human clinical condition. They assessed the following hypotheses: 1) that they will be able to consistently produce an internal carotid artery (ICA) terminus infarction and 2) that tamoxifen is an effective neuroprotectant against stroke in canines.Methods. In 24 male beagles (weight 9-11 kg), bilateral femoral artery cutdowns were performed, and the vertebral artery and left ICA were each selectively catheterized. Under fluoroscopic guidance, a microcatheter was introduced via the vertebral artery, guiding the catheter into the basilar artery, posterior communicating artery, and ICA terminus: A 1-ml clot was injected in the terminus, occluding the middle cerebral artery (MCA) and anterior cerebral artery (ACA) origin. In the first 12 canines, the occlusions were confirmed by angiography. A Canine Stroke Score (CSS) was assigned (score range 0-18 [0 = intact on examination, 18 = comatose)). The animals were then killed and their brains stained with 2,3,5-triphenyltetrazolium chloride (TTC). The subsequent 12 canines underwent a blinded randomized study in which the authors compared the results of tamoxifen (5 mg/kg) infused intravenously 1 hour after clot injection with an equal volume of vehicle (dimethylsulfoxide). After 3 hours, the animals underwent MR imaging, were extubated, and clinical examinations were performed. The canines were killed at 8 hours after clot injection, and TTC staining was used.Results. In the first group, infarct volume and CSSs were consistent with the extent of the occlusion of the angiographic vessels. An occlusion of the ACA, MCA, and posterior cerebral artery resulted in larger infarcts and higher stroke scores than occlusion of the ACA and MCA. In the second group, tamoxifen significantly reduced infarct size and improved clinical outcomes. In tamoxifen-treated animals, the mean infarct volume reduction was 40% (p < 0.05) and the mean CSS was significantly less than vehicle-treated animals (p < 0.001). There were significant correlations among MR imaging-determined volume, TTC-determined volume, and neurological clinical outcome (p < 0.05).Conclusions. Using this endovascular model of stroke, the authors were able to consistently produce an infarction in the canines that was similar in scope to a carotid terminus occlusion in humans. Also, angiography could predict subsequent clinical course and infarct size. Tamoxifen was effective at significantly improving the canine neurological deficits and reducing the size of the stroke. This study took the first step in demonstrating the effectiveness of a promising human neuroprotectant in a large animal. (DOI: 10.3171/2010.8.JNS09352)