Key Laboratory of Integrative Biomedicine for Brain Diseases, School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; National Famous Chinese Medicine Expert Inheritance Studio (Meng Jingchun), Nanjing University of Chinese Medicine, School of Chinese Medicine, Nanjing 210023, PR China.
Interdisciplinary Institute for Personalized Medicine in Brain Disorders, Jinan University, Guangzhou 510632, PR China.
Phytomedicine. 2024 Aug;131:155802. doi: 10.1016/j.phymed.2024.155802. Epub 2024 Jun 4.
Alzheimer's disease (AD) is a serious neurodegenerative disease and brings a serious burden to society and families. Due to lack of effective drugs for the treatment of AD, it's urgent to develop new and effective drug for the treatment of AD.
The study aimed to investigate the potential of Zexieyin formula (ZXYF), a Chinese medicine formula, for the treatment of AD and its potential mechanism of action.
We used chronic scopolamine (SCOP) induction mice model and APP/PS1 mice to reveal and confirm ZXYF for the treatment of AD with donepezil (DON) as a positive reference. The learning and memory function were detected by morris water maze test (MWM) and y-maze test. Moreover, western blot and immunofluorescence were used to detect the molecular mechanism of ZXYF for the alleviation of AD in hippocampus. Lastly, pharmacological technology was applied to evaluate AMPA receptor involved in the role of ZXYF in the treatment of AD.
The results showed that ZXYF could improve memory and learning deficits both in two AD models including scopolamine (SCOP)-induced mice model and APP/PS1mice. Moreover, ZXYF or not DON increased expressions of BrdU/DCX and Ki67 positive cells in dentate gyrus (DG), up-regulated the levels of AMPA subunit type (GluA1) and PKA in hippocampus in SCOP-induced mice model, although ZXYF and DON activated CaMKII, CaMKII-phosphorylation, CREB, CREB-phosphorylation and PSD95 in hippocampus in SCOP-induced mice model. ZXYF also activated CaMKII, CaMKII-phosphorylation and GluA1 in HT22 cells. Furthermore, transient inhibiting AMPA receptor was capable of blocking the effects of ZXYF to treat AD in MWM and suppressing the number of BrdU/DCX positive cells increased by ZXYF in DG in SCOP-induced mice model, but had no effect on the alteration of Ki67 positive cells.
ZXYF had the therapeutic effects on AD-treatment, which activated CaMKII to promote AMPA receptor (GluA1) and subsequently up-regulated PKA/CREB signaling to facilitate neurogenesis to achieve enhanced postsynaptic protein.
阿尔茨海默病（AD）是一种严重的神经退行性疾病，给社会和家庭带来了严重的负担。由于缺乏有效的 AD 治疗药物，因此迫切需要开发新的有效的 AD 治疗药物。
本研究旨在探讨中药方剂泽泻饮（ZXYF）治疗 AD 的潜力及其可能的作用机制。
我们使用慢性东莨菪碱（SCOP）诱导的小鼠模型和 APP/PS1 小鼠，以多奈哌齐（DON）作为阳性对照，揭示和证实 ZXYF 治疗 AD 的作用。通过 Morris 水迷宫试验（MWM）和 Y 迷宫试验检测学习和记忆功能。此外，通过 Western blot 和免疫荧光检测 ZXYF 缓解 AD 中海马分子机制。最后，应用药理学技术评价 ZXYF 治疗 AD 中 AMPA 受体的作用。
结果表明，ZXYF 可改善 SCOP 诱导的小鼠模型和 APP/PS1 小鼠两种 AD 模型的记忆和学习障碍。此外，ZXYF 或 DON 增加了 SCOP 诱导的小鼠模型齿状回（DG）中 BrdU/DCX 和 Ki67 阳性细胞的表达，上调了海马中的 AMPA 亚基类型（GluA1）和蛋白激酶 A（PKA）水平，尽管 ZXYF 和 DON 激活了 SCOP 诱导的小鼠模型中海马中的 CaMKII、CaMKII 磷酸化、CREB、CREB 磷酸化和突触后密度蛋白 95（PSD95）。ZXYF 还激活了 HT22 细胞中的 CaMKII、CaMKII 磷酸化和 GluA1。此外，瞬时抑制 AMPA 受体可阻断 ZXYF 治疗 MWM 中 AD 的作用，并抑制 SCOP 诱导的小鼠模型中 ZXYF 增加的 DG 中 BrdU/DCX 阳性细胞的数量，但对 Ki67 阳性细胞的变化没有影响。
ZXYF 对 AD 治疗具有治疗作用，它激活 CaMKII 以促进 AMPA 受体（GluA1），并随后上调蛋白激酶 A/环磷酸腺苷反应元件结合蛋白（PKA/CREB）信号通路，促进神经发生，从而增强突触后蛋白。
