Osthole ameliorates cognitive impairment in ovariectomized rats via estrogen-mediated enhancement of cholinergic function and regulation of neurotransmitter homeostasis

IF 4.7 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2026-03-15 Epub Date: 2025-12-12 DOI:10.1016/j.neuropharm.2025.110806

Yanman Liu , Jimei Zhang , Wenjuan Li , Qingwen Qu , Zhengxing Shan , Chunwei Liu , Ke Jiao , Xueqin Hou

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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen–cholinergic–NGF axis: E₂, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.

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蛇床子素通过雌激素介导的增强胆碱能功能和调节神经递质稳态改善去卵巢大鼠认知功能障碍。

阿尔茨海默病（AD）是一种以认知功能障碍为特征的进行性神经退行性疾病，与胆碱能系统损伤密切相关。雌激素缺乏是女性AD的一个公认的危险因素。蛇草素（OST）是一种温和的植物雌激素，具有双向调节特性，被认为是一种潜在的雌激素替代品。本研究旨在探讨OST改善认知障碍的机制。雌性Sprague-Dawley大鼠双侧卵巢切除术（OVX）诱导认知障碍，OST随后灌胃。行为测试显示，OST显著改善OVX大鼠的学习和记忆，减少焦虑样和抑郁样行为。H&E染色和Nissl染色表明，OST逆转了海马和皮层的神经元损伤。Western blotting、ELISA和免疫荧光染色显示，OST处理恢复了雌激素-胆碱能- ngf轴：E2、ERα和ERβ表达上调；Ach、ChAT、NGF和TrkA水平升高，AChE活性降低。此外，OST通过提高Bcl-2和降低Bax的表达，增强突触可塑性标志物（PSD95、SYN和BDNF）的表达，调节神经递质释放（GABA和E）来抑制神经元凋亡。总的来说，这些多靶点效应确定OST是治疗女性AD的有希望的候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).