Targeted delivery of Neurogenin-2 protein in the treatment for cerebral ischemia-reperfusion injury

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• 作者：Bin Deng ; Xingchun Gou ; Hai Chen ; Liya Li ; Haixing Zhong ; Hao Xu ; Fengliang Jiang ; Zhijing Zhao ; Qiang Wang ; Lixian Xu
• 关键词：Stroke ; Neurogenin-2 ; Trans-activator of transcription domain ; Laminin-binding domain ; Targeted delivery ; Apoptosis
• 刊名：Biomaterials
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：34
• 期：34
• 页码：8786-8797
• 全文大小：4821 K

文摘

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.