Targeted delivery of Neurogenin-2 protein in the treatment for cerebral ischemia-reperfusion injury
Targeted delivery of Neurogenin-2 protein in the treatment for cerebral ischemia-reperfusion injury
复制标题
Neurogenin-2蛋白靶向递送治疗脑缺血再灌注损伤
DOI：
10.1016/j.biomaterials.2013.07.076
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发表时间：
2013-11-01
期刊：
影响因子：
14
通讯作者：
Xu, Lixian
中科院分区：
文献类型：
--
作者：
Deng, Bin;Gou, Xingchun;Xu, Lixian
神经生长素-2(Neurogenin-2，Ngn2)作为一种促进神经前体细胞存活和分化的神经原基因，是治疗脑缺血再灌注损伤的候选基因。然而，这种给药方式限制了其临床应用。为了将Ngn2蛋白转移到脑缺血区，并对缺血后受损的神经元起到治疗作用，我们报道了将转录反式激活因子(TAT)结构域和层粘连蛋白结合结构域(LBD)融合到Ngn2上，构建了TAT-LBD-Ngn2融合蛋白。TAT-LBD-Ngn2可促进体外培养的缺氧缺糖海马神经元突起生长，提高存活率，减轻细胞凋亡。此外，C57BL/6小鼠局灶性脑缺血模型显示，TAT-LBD-Ngn2有效地穿过血脑屏障，聚集在缺血区，并持续整合到神经元中。此外，TAT-LBD-Ngn2转导到脑内可减轻缺血区神经元的变性和凋亡。TAT-LBD-Ngn2治疗导致了梗塞体积的减少，这与再灌注后神经功能结果的平行改善有关。结论：TAT-LBD-Ngn2靶向缺血区可通过抑制神经元变性和细胞凋亡而减轻脑缺血再灌注损伤，提示TAT-LBD-Ngn2有望成为治疗缺血性卒中的靶点。(C)2013爱思唯尔有限公司。保留所有权利。
Neurogenin-2 (Ngn2), as a proneural gene that promotes the survival and differentiation of neural precursor cells, is an attractive candidate for therapy against cerebral ischemia-reperfusion injury. However, the delivery approach limits its clinical application. To deliver Ngn2 protein into the cerebral ischemic region and exert a therapeutic effect on injured neurons after ischemia, we here reported that the fusion protein TAT-LBD-Ngn2 was constructed by fusing a transactivator of transcription (TAT) domain and a laminin-binding domain (LBD) to Ngn2. TAT-LBD-Ngn2 promoted the outgrowth of neuronal neurite, increased the survival rate and alleviated apoptosis of hippocampal neurons exposed to oxygen glucose deprivation in vitro. Furthermore, a focal cerebral ischemia model in C57BL/6 mice showed that TAT-LBD-Ngn2 efficiently crossed the blood brain barrier, aggregated in the ischemic zone and was consistently incorporated into neurons. Moreover, TAT-LBD-Ngn2 transduced into brains attenuated neuronal degeneration and apoptosis in the ischemic zone. TAT-LBD-Ngn2 treatment resulted in a reduction of infarct volume that was associated with a parallel improvement in neurological functional outcomes after reperfusion. In conclusion, the targeted delivery of TAT-LBD-Ngn2 into the ischemic zone attenuated cerebral ischemia-reperfusion injury through the inhibition of neuronal degeneration and apoptosis, suggesting that TAT-LBD-Ngn2 is a promising target candidate for the treatment of ischemic stroke. (C) 2013 Elsevier Ltd. All rights reserved.