ev介导的CB2受体激动剂用于阿尔茨海默病治疗

IF 10.7 1区 医学 Q1 PHARMACOLOGY & PHARMACY Asian Journal of Pharmaceutical Sciences Pub Date : 2023-07-01 DOI:10.1016/j.ajps.2023.100835
Yanjing Zhu , Ruiqi Huang , Deheng Wang , Liqun Yu , Yuchen Liu , Runzhi Huang , Shuai Yin , Xiaolie He , Bairu Chen , Zhibo Liu , Liming Cheng , Rongrong Zhu
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引用次数: 2

摘要

阿尔茨海默病(AD)是一种典型的神经退行性疾病,可导致不可逆的神经元变性,由于其机制尚不清楚,有效的治疗方法仍然难以捉摸。我们利用生物相容性间充质干细胞衍生的细胞外小泡作为负载CB2靶向药物AM1241(EVs-AM1241)的载体,来保护AD模型小鼠免受神经退行性进展和神经元功能的影响。根据结果,EVs-AM1241被成功构建,并表现出比裸AM1241更好的生物利用度和治疗效果。Morris水迷宫(MWM)和恐惧条件测试显示,EVs-AM1241处理的模型小鼠的学习和记忆显著改善。CA1神经元的体内电生理记录表明,恐惧学习后对听觉条件刺激的反应增强。免疫染色和蛋白质印迹分析显示,EVs-AM1241显著抑制淀粉样斑块沉积和淀粉样β(Aβ)诱导的神经元凋亡。此外,EVs-AM1241增加了神经元数量并恢复了神经元细胞骨架,表明它们增强了神经元再生。RNA测序显示,EVs-AM1241通过钙Erk信号通路促进Aβ吞噬作用,促进神经发生,并最终改善学习和记忆。我们的研究表明,EVs-AM1241有效地逆转了模型小鼠的神经退行性病理并增强了神经发生,表明它们是治疗AD的非常有前景的颗粒。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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EVs-mediated delivery of CB2 receptor agonist for Alzheimer's disease therapy

Alzheimer's disease (AD) is a typical neurodegenerative disease that leads to irreversible neuronal degeneration, and effective treatment remains elusive due to the unclear mechanism. We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241 (EVs-AM1241) to protect against neurodegenerative progression and neuronal function in AD model mice. According to the results, EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241. The Morris water maze (MWM) and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved. In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning. Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloid β (Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241. Moreover, EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton, indicating that they enhanced neuronal regeneration. RNA sequencing revealed that EVs-AM1241 facilitated Aβ phagocytosis, promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway. Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in model mice, indicating that they are very promising particles for treating AD.

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来源期刊
Asian Journal of Pharmaceutical Sciences
Asian Journal of Pharmaceutical Sciences Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
18.30
自引率
2.90%
发文量
11
审稿时长
14 days
期刊介绍: The Asian Journal of Pharmaceutical Sciences (AJPS) serves as the official journal of the Asian Federation for Pharmaceutical Sciences (AFPS). Recognized by the Science Citation Index Expanded (SCIE), AJPS offers a platform for the reporting of advancements, production methodologies, technologies, initiatives, and the practical application of scientific knowledge in the field of pharmaceutics. The journal covers a wide range of topics including but not limited to controlled drug release systems, drug targeting, physical pharmacy, pharmacodynamics, pharmacokinetics, pharmacogenomics, biopharmaceutics, drug and prodrug design, pharmaceutical analysis, drug stability, quality control, pharmaceutical engineering, and material sciences.
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