过刊浏览

硫酸酯酶抑制剂DU-14拮抗β-淀粉样蛋白改善大鼠海马theta节律及抑郁表现

岳兴华^1,*, 王昭君², 武美娜², 蔡红艳³, 张军²

¹天津中医药大学第一附属医院，国家中医针灸临床医学研究中心，天津 300193；²山西医科大学生理学系，细胞生理学省部共建教育部重点实验室，太原 030001；³山西医科大学微生物与免疫教研室，太原 030001

摘要

海马体作为边缘系统的重要组成部分参与学习记忆及情绪调节。阿尔茨海默病患者的认知功能减退及抑郁表现可能与β-淀粉样蛋白(amyloid β-protein, Aβ)对海马的损伤有关。我们既往研究发现硫酸酯酶抑制剂DU-14 可以通过拮抗Aβ毒性，改善AD动物模型海马突触可塑性并提高其空间记忆能力，但对DU-14是否可以改善AD动物模型的抑郁表现尚缺乏实验证据。本研究利用糖水偏好实验、悬尾实验、强迫游泳实验和在体海马局部场电位记录技术，观察了海马注射DU-14对Aβ1-42海马注射诱导AD大鼠模型的抑郁表现及theta节律神经振荡活动的影响。结果显示，与对照组相比，海马注射Aβ1-42寡聚体两周后：(1)大鼠对愉悦活动的兴趣减弱，在糖水偏好实验中糖水偏好指数降低；(2)大鼠绝望抑郁情绪增加，在悬尾实验及强迫游泳实验中消极不动时间增加；(3)大鼠海马theta节律神经振荡活动减弱，其功率值减低。DU-14 + Aβ组大鼠与Aβ组大鼠相比：(1)海马注射DU-14有效缓解了Aβ诱导的大鼠快感缺乏，糖水偏好指数升高；(2)海马注射DU-14有效降低了Aβ诱导的大鼠绝望抑郁表现，悬尾实验及强迫游泳实验中不动时间减少；(3)海马注射DU-14有效阻断了Aβ对大鼠双侧海马theta节律神经振荡活动的压抑。以上结果表明，硫酸酯酶抑制剂DU-14可拮抗Aβ神经毒性，解除其对海马theta节律神经振荡的压抑，并改善AD动物模型的抑郁表现。

关键词： β-淀粉样蛋白; 硫酸酯酶抑制剂; 抑郁; 阿尔茨海默病; theta节律

Steroid sulfatase inhibitor DU-14 prevents amyloid β-protein-induced depressive-like behavior and theta rhythm suppression in rats

YUE Xing-Hua^1,*, WANG Zhao-Jun², WU Mei-Na², CAI Hong-Yan³, ZHANG Jun²

¹First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300193, China；²Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China；³Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China

Abstract

The hippocampus, a major component of the limbic system, is the most important region related to emotion regulation and memory processing. Cognitive impairment and depressive symptoms observed in Alzheimer's disease (AD) patients may be attributed to hippocampal damage caused by amyloid β-protein (Aβ). Our previous studies have demonstrated that a steroid sulfatase inhibitor DU-14 can enhance hippocampal synaptic plasticity and spatial memory abilities in a chronic AD murine model by counteracting the toxic effects of Aβ. However, limited experimental evidence exists regarding the efficacy of steroid sulfatase inhibitor on depressive symptoms in AD animal models. In this study, we investigated the effects of DU-14 on depressive symptoms and theta-band neuronal oscillations in rats with intrahippocampal injection of Aβ1-42 using various behavioral tests such as sucrose preference test, tail suspension test, forced swimming test, and in vivo hippocampal local field potential (LFP) recording. The results demonstrated that, in comparison to the control group: (1) rats in the Aβ group exhibited a decrease in sucrose preference, indicating a loss of interest in pleasurable activities; (2) rats in the Aβ group displayed aggravated depressive-like behavior characterized by prolonged immobility time during tail suspension and forced swimming tests; (3) Aβ disrupted the induction of theta rhythm via tail pinch stimulation, and resulted in a significant reduction in peak power of theta rhythm. In contrast to the Aβ group, pretreatment with DU-14 resulted in: (1) a significant improvement in Aβ-induced anhedonia, as evidenced by increased sucrose preference; (2) significant alleviation of Aβ-induced despair and depressive-like behaviors, reflected by reduced immobility time during tail suspension and forced swimming tests; (3) successful mitigation of Aβ-mediated inhibition on bilateral hippocampal theta rhythm. These findings indicate that steroid sulfatase inhibitor DU-14 can counteract neurotoxicity induced by Aβ, and prevent Aβ-induced depressive-like behavior and suppression of theta rhythm.

Key words: amyloid β-protein; steroid sulfatase inhibitor; depression; Alzheimer''s disease; theta rhythm

收稿日期：　　录用日期：

通讯作者：岳兴华　　E-mail:

DOI: 10.13294/j.aps.2025.0052

引用本文：

岳兴华, 王昭君, 武美娜, 蔡红艳, 张军. 硫酸酯酶抑制剂DU-14拮抗β-淀粉样蛋白改善大鼠海马theta节律及抑郁表现[J]. 生理学报 2025; 77 (5): 801-810.

YUE Xing-Hua, WANG Zhao-Jun, WU Mei-Na, CAI Hong-Yan, ZHANG Jun. Steroid sulfatase inhibitor DU-14 prevents amyloid β-protein-induced depressive-like behavior and theta rhythm suppression in rats. Acta Physiol Sin 2025; 77 (5): 801-810 (in Chinese with English abstract).