Neuroprotective activity of tamoxifen in permanent focal ischemia
Neuroprotective activity of tamoxifen in permanent focal ischemia
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DOI：
10.3171/jns.2003.99.1.0138
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发表时间：
2003-07-01
影响因子：
4.1
通讯作者：
Feustel, PJ
中科院分区：
文献类型：
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作者：
Kimelberg, HK;Jin, YQ;Feustel, PJ
物体。作者先前已经证明他莫昔芬在可逆性局灶性脑缺血大鼠模型中有效地保护脑组织免受缺血损伤。在这项研究中，作者测试了在永久性局灶性脑缺血(永久性大脑中动脉闭塞)的大鼠模型中是否发现了类似的保护作用。在永久性大脑中动脉闭塞前、后1、3或6小时给予他莫昔芬(20 mg/kg)，此后每12小时持续给药一次。溶剂组72小时后测得的中位脑梗塞体积为113 mm(3)，而预处理组为31 mm(3)，永久性MCA闭塞后1、3和6小时开始的治疗组分别为14、27和98 mm。治疗前、大脑中动脉闭塞后1小时和3小时组的脑梗塞缩小有统计学意义(p<；0.05)。在永久性大脑中动脉闭塞后3h，他莫昔芬在5 mg/kg的低剂量下也能显著缩小脑梗塞面积，但在1 mg/kg时无明显作用；同样的维持剂量5 mg/kg和1 mg/kg每12小时给药一次。他莫昔芬在永久性局灶性缺血模型中与在可逆性模型中一样有效，缺血开始后3小时的治疗窗口是相同的。这种有效性可能是由于这种药物的几种特性，包括它已知的穿越血脑屏障的能力。由于他莫昔芬在人类治疗胶质瘤中的安全性与本研究中使用的高剂量相似，因此它可能在临床上用于治疗缺血性中风。
Object. The authors have previously shown that tamoxifen is effective in protecting brain tissue from ischemic injury in a rat model of reversible focal ischemia. In this study the authors tested whether similar protective effects are found in a rat model of permanent focal ischemia (permanent middle cerebral artery [MCA] occlusion).Methods. Tamoxifen (20 mg/kg) was given either before or at 1, 3, or 6 hours after permanent MCA occlusion in rats, with sustaining doses given every 12 hours thereafter. The median infarct volume measured after 72 hours was 113 mm(3) for the vehicle (dimethyl sulfoxide) groups, compared with 31 mm(3) for pretreatment, and 14, 27, and 98 mm for treatment beginning at 1, 3, and 6 hours, respectively, after permanent MCA occlusion. The infarct reductions in the pretreated and 1- and 3-hour post-MCA occlusion treatment groups were statistically significant (p < 0.05). At 3 hours after permanent MCA occlusion, tamoxifen also significantly reduced the infarct size at a lower dose of 5 mg/kg but not at 1 mg/kg; the same sustaining doses of 5 and I mg/kg were given every 12 hours.Conclusions. Tamoxifen is as effective in a permanent model of focal ischemia as it is in the reversible model, and the therapeutic window of 3 hours after initiation of ischemia is identical. This effectiveness is likely due to several properties of the drug, including its known ability to cross the blood-brain barrier. Because tamoxifen has been administered safely in humans for treatment of gliomas at similarly high doses to those used in this study, it may be clinically useful as a treatment for ischemic stroke.