Lin Shiguo, Ye Yanshan, Lin Sujin
Department of Psychiatry, Wenzhou Seventh People's Hospital, Wenzhou, Zhejiang, 325000, P. R. China.
Department of Rehabilitation, Wenzhou TCM Hospital of Zhejiang Chinese Medical University, Wenzhou, Zhejiang, 325000, P. R. China.
Open Life Sci. 2025 Mar 18;20(1):20221043. doi: 10.1515/biol-2022-1043. eCollection 2025.
Rhynchophylline (Rhy) is an attractive candidate, harboring ameliorative effects on Alzheimer's disease (AD). Nevertheless, its application is impeded by its low water solubility and poor bioavailability. Here we synthesized and characterized the Rhy-loaded hyaluronic acid-modified hafnium metal-organic frameworks (HA@Rhy@Hf-MOF). The drug release profiles of free Rhy from HA@Rhy@Hf-MOF were evaluated, and the cellular toxicity was assessed through Cell Counting Kit-8 (CCK-8) assay. experiments included behavioral experiments of various murine capabilities, with neuronal damage appraised through Hematoxylin and Eosin staining and Nissl staining. Subsequently, the formation of AD-related amyloid beta (Aβ) plaques formation and Tau phosphorylation were measured. The HA@Rhy@Hf-MOF with spherical shape were presented as uniformly dispersed and with a negative charge, exhibiting a pronounced pharmacological sustained-release effect and minimal cellular toxicity. Findings from the Morris water maze test, novel object recognition test, and elevated plus maze test substantiated that HA@Rhy@Hf-MOF effectively mitigated cognitive deficiency and anxiety, and enhanced spatial learning in AD mice. Immunofluorescence staining and Western blot both illustrated that HA@Rhy@Hf-MOF could attenuate hippocampal Aβ formation and deposition, as well as tau hyperphosphorylation. In conclusion, HA@Rhy@Hf-MOF exerts its therapeutic efficacy against AD by targeting the deposition of Aβ plaques and inhibiting site-specific phosphorylation of Tau.
钩藤碱（Rhy）是一种有吸引力的候选药物，对阿尔茨海默病（AD）具有改善作用。然而，其应用受到低水溶性和差生物利用度的阻碍。在此，我们合成并表征了负载钩藤碱的透明质酸修饰的铪金属有机框架（HA@Rhy@Hf-MOF）。评估了HA@Rhy@Hf-MOF中游离钩藤碱的药物释放曲线，并通过细胞计数试剂盒-8（CCK-8）测定法评估细胞毒性。实验包括各种小鼠能力的行为实验，通过苏木精和伊红染色以及尼氏染色评估神经元损伤。随后，测量AD相关的淀粉样β（Aβ）斑块的形成和Tau磷酸化。呈球形的HA@Rhy@Hf-MOF表现为均匀分散且带负电荷，具有明显的药理缓释作用和最小的细胞毒性。莫里斯水迷宫试验、新物体识别试验和高架十字迷宫试验的结果证实，HA@Rhy@Hf-MOF有效减轻了AD小鼠的认知缺陷和焦虑，并增强了空间学习能力。免疫荧光染色和蛋白质印迹均表明，HA@Rhy@Hf-MOF可减轻海马Aβ的形成和沉积以及tau过度磷酸化。总之，HA@Rhy@Hf-MOF通过靶向Aβ斑块的沉积并抑制Tau的位点特异性磷酸化发挥其对AD的治疗功效。
