Chen Yan, Zhu Yan, Tan Zihu, Zhang Xueyi, Hu Jiafeng, Zhu Ruichi, Xie Minjie, Wang Jing, Chen Lizhu, Guo Zhenli
Department of Neurology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, No. 11 Lingjiaohu Road, Wuhan, Hubei, 430015, China.
Wuhan No.1 Hospital, Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, Hubei, 430015, China.
J Ethnopharmacol. 2025 Mar 13;343:119508. doi: 10.1016/j.jep.2025.119508. Epub 2025 Feb 17.
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments in the elderly. Microglia, the resident immune cells of the central nervous system, play a crucial role in modulating the pathological processes associated with AD. Jiajian Shuyu Pills (JJSYP) are frequently employed in the treatment of AD, purportedly by enhancing the physiological functions of human tissues and organs to modulate the immune response. Nevertheless, the underlying mechanisms by which JJSYP exert their therapeutic effects in the context of AD remain inadequately elucidated.
This study aimed to assess the effects of JJSYP on cognitive enhancement and the alleviation of neuroinflammation in the treatment of AD, as well as to explore the underlying mechanisms using mouse models.
The components of JJSYP in serum were analyzed using HPLC-Q/TOF-MS. APP/PS1 transgenic mice served as AD models in this investigation. Cognitive function in the AD mice was assessed through the Mirror Water Maze Test and the Novel Object Recognition Test. The quantification of apoptotic hippocampal cells was conducted using Nissl staining and TUNEL staining. Immunofluorescence (IF) and Western blot (WB) analyses were employed to examine microglial activation and the expression of relevant proteins. Transcriptomic sequencing analysis and network pharmacology were administrated to explore the potential mechanisms of JJSYP in AD treatment. Inflammatory cytokine levels in the brain were measured using RT-PCR.
A total of 74 absorbed prototype components from JJSYP were identified. JJSYP effectively improved cognitive function and neuroapoptosis in AD model mice by modulating the activation of microglia. The JJSYP intervention alleviated neuroinflammation by suppressing microglial activation and reducing the accumulation of amyloid β-protein. Through transcriptome sequencing and WB verification, 34 differentially expressed genes (DEGs) were identified, including ACKR3, NR1H3 and Adra1a. Following treatment with a high dose of JJSYP, both ACKR3 and NR1H3 showed a significant decrease compared to the model group. Conversely, ADRA1A expression was reduced in model group compared to the control group, but increased following high dose JJSYP treatment. Research involving RNA sequencing and network pharmacology indicated that JJSYP altered the activation of CXCL12/ACKR3 signaling pathways in the hippocampus.
JJSYP exhibits potential anti-Alzheimer's Disease effects and warrants further investigation and development as a prosper treatment for AD.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征为老年人出现进行性认知衰退和行为障碍。小胶质细胞作为中枢神经系统中的常驻免疫细胞，在调节与AD相关的病理过程中发挥着关键作用。加减首乌玉液丸（JJSYP）常用于AD的治疗，据称是通过增强人体组织和器官的生理功能来调节免疫反应。然而，JJSYP在AD背景下发挥治疗作用的潜在机制仍未得到充分阐明。
本研究旨在评估JJSYP在AD治疗中对认知增强和神经炎症缓解的作用，并利用小鼠模型探索其潜在机制。
采用高效液相色谱-四极杆飞行时间质谱联用（HPLC-Q/TOF-MS）分析血清中JJSYP的成分。本研究中使用APP/PS1转基因小鼠作为AD模型。通过镜像水迷宫试验和新物体识别试验评估AD小鼠的认知功能。使用尼氏染色和TUNEL染色对海马凋亡细胞进行定量分析。采用免疫荧光（IF）和蛋白质免疫印迹（WB）分析来检测小胶质细胞的激活情况和相关蛋白的表达。进行转录组测序分析和网络药理学研究以探索JJSYP在AD治疗中的潜在机制。使用逆转录聚合酶链反应（RT-PCR）检测脑中炎性细胞因子水平。
共鉴定出74种JJSYP的吸收原型成分。JJSYP通过调节小胶质细胞的激活，有效改善了AD模型小鼠的认知功能和神经细胞凋亡。JJSYP干预通过抑制小胶质细胞激活和减少淀粉样β蛋白的积累减轻了神经炎症。通过转录组测序和WB验证，鉴定出34个差异表达基因（DEGs），包括ACKR3、NR1H3和Adra1a。高剂量JJSYP治疗后，与模型组相比，ACKR3和NR1H3均显著降低。相反，与对照组相比，模型组中ADRA1A表达降低，但高剂量JJSYP治疗后表达增加。涉及RNA测序和网络药理学的研究表明，JJSYP改变了海马中CXCL12/ACKR3信号通路的激活。
JJSYP具有潜在的抗阿尔茨海默病作用，作为一种有前景的AD治疗药物值得进一步研究和开发。
