Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia
Brain protection using autologous bone marrow cell, metalloproteinase inhibitors, and metabolic treatment in cerebral ischemia
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DOI：
10.1073/pnas.0611112104
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发表时间：
2007-02-27
影响因子：
11.1
通讯作者：
Napoli, Claudio
中科院分区：
文献类型：
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作者：
Baker, Andrew H.;Sica, Vincenzo;Napoli, Claudio
尽管在成像、理解潜在途径和疾病动物模型的临床转化方面取得了进展，但仍然迫切需要减少中风后脑损伤并促进患者功能恢复的疗法。阻断氧化剂自由基，减少基质金属蛋白酶-included神经元损伤，和使用干细胞治疗已经提出并在先前的研究中单独测试。在这里，我们提供了一个全面的综合管理方法，以减少损害和促进恢复，结合针对这些领域的生物疗法。在短暂性脑缺血（大脑中动脉闭塞）的大鼠模型中，在缺血前3天使用基因递送载体过表达基质金属蛋白酶组织抑制剂1和2（TIMP 1和TIMP 2）。闭塞后，自体骨髓细胞单独或与提高NO生物利用度的药物联合动脉内给药。当在治疗组中确定梗死面积、BrdU掺入和运动功能恢复时，在接受三联疗法的大鼠中观察到最大的有益效果，超过了单药或双药疗法的效果。我们的研究强调了联合药物、基因和细胞疗法在治疗中风中的效用。
Despite advances in imaging, understanding the underlying pathways, and clinical translation of animal models of disease there remains an urgent need for therapies that reduce brain damage after stroke and promote functional recovery in patients. Blocking oxidant radicals, reducing matrix metal loproteinase-incluced neuronal damage, and use of stem cell therapy have been proposed and tested individually in prior studies. Here we provide a comprehensive integrative management approach to reducing damage and promoting recovery by combining biological therapies targeting these areas. In a rat model of transient cerebral ischemia (middle cerebral artery occlusion) gene delivery vectors were used to overexpress tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1 and TIMP2) 3 days before ischemia. After occlusion, autologous bone marrow cells alone or in combination with agents to improve NO bioavailability were administered intraarterially. When infarct size, BrdU incorporation, and motor function recovery were determined in the treatment groups the largest beneficial effect was seen in rats receiving the triple combined therapy, surpassing effects of single or double therapies. Our study highlights the utility of combined drug, gene, and cell therapy in the treatment of stroke.