Yu Tianhao, Yu Ying, Zhao Junqi, Li He, Lu Hui, Li Yangyi, Peng Yuqi, Wang Shixue, Wei Wendi, Cheng Xiaorui
Institute of Innovation in Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
Front Psychiatry. 2025 May 14;16:1554866. doi: 10.3389/fpsyt.2025.1554866. eCollection 2025.
Alzheimer's disease (AD) is frequently accompanied by behavioral and psychological symptoms of dementia (BPSD). Studies have shown that 3×Tg-AD mice, a classical animal model of AD, exhibit anxiety and depression-like behaviors characteristic of BPSD.
This study investigated the effects of Qifuyin on anxiety and depression-like behaviors in 3×Tg-AD mice.
The 20 male and female C57BL/6 mice at 10.3 months of age were used as the control group, while the 82 male and female 3×Tg-AD mice of the same age were divided into five groups. The control and model groups were gavaged with solvent, the positive medicine group received a combination of donepezil and memantine, and the Qifuyin (QFY) groups were divided into three doses: low, medium, and high. The effects of QFY on anxiety-like behaviors in mice were assessed using the open field test (OFT) and elevated plus maze (EPM) test, while depression-like behaviors were evaluated through the forced swim test (FST) and sucrose splash test (ST). Plasma levels of corticosterone (CORT), testosterone (T), and estradiol (E2) were measured using ELISA, while adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), corticotropin-releasing hormone (CRH), and gonadotropin-releasing hormone (GnRH) were quantified via radioimmunoassay. Differences in plasma hormone levels among groups were analyzed using principal component analysis (PCA). Pearson correlation analysis was conducted to explore the relationships between plasma hormones and behavioral phenotypes, and multiple linear regression was employed to identify the hormones most strongly correlated with anxiety and depression-like behaviors in mice following QFY treatment.
In 3×Tg-AD mice, anxiety-like behaviors were characterized by reduced the duration, number of visits, and total distances in central area during the OFT. The EPM revealed reduced the duration and frequency in the open arms for both sexes. Depression-like behaviors were evident in the FST, with increased immobility, and in the ST, with prolonged grooming latency in both sexes and reduced grooming frequency in females. The treatment of QFY alleviated these behaviors. In males, In the model group, plasma ACTH, GnRH, and FSH levels were significantly decreased. In the QFY-treated group, plasma CRH levels were significantly reduced, while GnRH levels were significantly increased. In the model group of females, plasma ACTH levels were significantly elevated, while FSH and LH levels were markedly reduced. In the QFY-treated group, plasma CORT levels were significantly decreased, whereas FSH and LH levels were significantly increased. Multiple linear regression indicated QFY mainly mitigates anxiety and depression-like symptoms through modulating GnRH in males and T and ACTH in females.
The administration of QFY alleviates anxiety and depression in 3×Tg-AD mice by regulating the HPA, HPT and HPO axes.
阿尔茨海默病（AD）常伴有痴呆的行为和心理症状（BPSD）。研究表明，3×Tg-AD小鼠作为AD的经典动物模型，表现出BPSD特有的焦虑和抑郁样行为。
本研究探讨芪附饮对3×Tg-AD小鼠焦虑和抑郁样行为的影响。
将20只10.3月龄的C57BL/6雌雄小鼠作为对照组，82只同年龄的3×Tg-AD雌雄小鼠分为五组。对照组和模型组灌胃溶剂，阳性药物组给予多奈哌齐和美金刚联合用药，芪附饮（QFY）组分为低、中、高三个剂量组。采用旷场试验（OFT）和高架十字迷宫（EPM）试验评估QFY对小鼠焦虑样行为的影响，通过强迫游泳试验（FST）和蔗糖偏好试验（ST）评估抑郁样行为。采用酶联免疫吸附测定法（ELISA）检测血浆皮质酮（CORT）、睾酮（T）和雌二醇（E2）水平，通过放射免疫分析法测定促肾上腺皮质激素（ACTH）、促卵泡生成素（FSH）、黄体生成素（LH）、促肾上腺皮质激素释放激素（CRH）和促性腺激素释放激素（GnRH）水平。使用主成分分析（PCA）分析各组血浆激素水平的差异。进行Pearson相关分析以探讨血浆激素与行为表型之间的关系，并采用多元线性回归确定QFY治疗后与小鼠焦虑和抑郁样行为最密切相关的激素。
在3×Tg-AD小鼠中，OFT显示焦虑样行为表现为中央区域停留时间、进入次数和总距离减少。EPM显示雌雄小鼠在开放臂的停留时间和频率均降低。FST中出现抑郁样行为，表现为不动时间增加，ST中雌雄小鼠理毛潜伏期延长，雌性小鼠理毛频率降低。QFY治疗可缓解这些行为。在雄性小鼠中，模型组血浆ACTH、GnRH和FSH水平显著降低。QFY治疗组血浆CRH水平显著降低，而GnRH水平显著升高。在雌性小鼠模型组中，血浆ACTH水平显著升高，而FSH和LH水平显著降低。QFY治疗组血浆CORT水平显著降低，而FSH和LH水平显著升高。多元线性回归表明，QFY主要通过调节雄性小鼠的GnRH以及雌性小鼠的T和ACTH来减轻焦虑和抑郁样症状。
芪附饮通过调节下丘脑-垂体-肾上腺（HPA）轴、下丘脑-垂体-甲状腺（HPT）轴和下丘脑-垂体-卵巢（HPO）轴，减轻3×Tg-AD小鼠的焦虑和抑郁。
