Treatment of ischemic neuronal death by introducing brain-derived neurotrophic factor mRNA using polyplex nanomicelle
Treatment of ischemic neuronal death by introducing brain-derived neurotrophic factor mRNA using polyplex nanomicelle
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DOI：
10.1016/j.biomaterials.2021.120681
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发表时间：
2021-01-28
期刊：
影响因子：
14
通讯作者：
Itaka, Keiji
中科院分区：
文献类型：
--
作者：
Fukushima, Yuta;Uchida, Satoshi;Itaka, Keiji
缺血性神经元死亡会导致严重的终生神经功能缺损；然而，尚无经过证实的有效治疗方法可以预防缺血后神经元死亡。我们研究了 mRNA 疗法预防短暂性全身缺血 (TGI) 大鼠模型中神经元死亡的可行性。通过使用基于聚合物的载体 Polyplex 纳米胶束向心室内注射编码脑源性神经营养因子 (BDNF) 的 mRNA，该 mRNA 显着提高了 TGI 后海马神经元的存活率，海马中 BDNF 迅速上升。有趣的是，TGI后第2天施用mRNA比TGI后立即施用提供了显着更好的存活率。最终，第 2 天和第 5 天两次给药产生了长期治疗效果，Y 迷宫行为测试证实了这一点，与第 20 天未治疗的大鼠相比，空间记忆得到改善。免疫组织化学分析表明，星形胶质细胞是负载 BDNF mRNA 的纳米胶束的主要目标，这表明星形胶质细胞 BDNF 分泌的增强为神经元创造了一个支持性微环境，以耐受缺血应激引起的变化，并终止神经元在缺血性应激后进行性死亡的过程。缺血性发作。总体而言，mRNA 疗法独特的作用机制为预防缺血性神经元死亡提供了一种有前景的方法。
Ischemic neuronal death causes serious lifelong neurological deficits; however, there is no proven effective treatment that can prevent neuronal death after the ischemia. We investigated the feasibility of mRNA therapeutics for preventing the neuronal death in a rat model of transient global ischemia (TGI). By intraventricular administration of mRNA encoding brain-derived neurotrophic factor (BDNF) using a polymer-based carrier, polyplex nanomicelle, the mRNA significantly increased the survival rate of hippocampal neurons after TGI, with a rapid rise of BDNF in the hippocampus. Interestingly, mRNA administration on Day 2 after TGI provided significantly better survival rate than the administration immediately after TGI. Eventually, dosing twice on Day 2 and 5 exerted long-term therapeutic effects, which were confirmed by a Y-maze behavioral test demonstrating improved spatial memory compared with untreated rats on Day 20. Immunohistochemical analysis showed that astrocytes were chief targets of the BDNF mRNA-loaded nanomicelles, suggesting that the augmented BDNF secretion from astrocytes creates a supportive microenvironment for the neurons to tolerate changes caused by ischemic stresses, and terminate the process of progressive neuronal death after the ischemic attack. Overall, the unique mechanism of action of mRNA therapeutics provide a promising approach for preventing ischemic neuronal death.