植物化学物质通过载脂蛋白E4/低密度脂蛋白受体相关蛋白1、Wnt3/β-连环蛋白/糖原合成酶激酶3β和Toll样受体4/NLRP3信号通路对氯化铝诱导的大鼠阿尔茨海默病模型产生神经保护作用并伴有身心活动。

Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer's Disease through ApoE4/LRP1, Wnt3/β-Catenin/GSK3β, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model.

作者信息

Hamdan Ahmed Mohsen Elsaid, Alharthi Fatimah Hussain J, Alanazi Ahmed Hadi, El-Emam Soad Z, Zaghlool Sameh S, Metwally Kamel, Albalawi Sana Abdulaziz, Abdu Yahia S, Mansour Reda El-Sayed, Salem Hoda A, Abd Elmageed Zakaria Y, Abu-Elfotuh Karema

机构信息

Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.

Graduate Pharmacist, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.

出版信息

Pharmaceuticals (Basel). 2022 Aug 17;15(8):1008. doi: 10.3390/ph15081008.

BACKGROUND

Alzheimer's disease (AD) is a neurodegenerative disorder that is associated with abnormal cognition. AD is aided in its initiation and progression by hereditary and environmental factors. Aluminum (Al) is a neurotoxic agent that causes oxidative stress, which is linked to AD progression. Additionally, Nrf2/HO-1, APOE4/LRP1, Wnt3/β-catenin, and TLR4/NLRP3 are the main signaling pathways involved in AD pathogenesis. Several phytochemicals are promising options in delaying AD evolution.

OBJECTIVES

This study aimed at studying the neuroprotective effects of some phytochemicals as morin (MOR), thymol (TML), and thymoquinone (TMQ) on physical and mental activities (PhM) in Al chloride (AlCl)-induced AD rat model. Another objective was to determine the specificity of phytochemicals to AD signaling pathways using molecular docking.

METHODS

Eighty male Dawley rats were divided into eight groups. Each group received: saline (control group), AlCl, (ALAD), PhM, either alone or with a combination of MOR, TML, and/or TMQ for five weeks. Animals were then subjected to behavioral evaluation. Brain tissues were used for histopathological and biochemical analyses to determine the extent of neurodegeneration. The effect of phytochemicals on AlCl-induced oxidative stress and the main signaling pathways involved in AD progression were also investigated.

RESULTS

AlCl caused a decline in spatial learning and memory, as well as histopathological changes in the brains of rats. Phytochemicals combined with PhM restored antioxidant activities, increased HO-1 and Nrf2 levels, blocked inflammasome activation, apoptosis, TLR4 expression, amyloide-β generation, and tau hyperphophorylation. They also brought ApoE4 and LRP1 levels back to normal and regulated Wnt3/β-catenin/GSK3β signaling pathway.

CONCLUSIONS

The use of phytochemicals with PhM is a promising strategy for reducing AD by modulating Nrf2/HO-1, TLR4/NLRP3, APOE4/LRP1, and Wnt3/β-catenin/GSK-3β signaling pathways.

背景

阿尔茨海默病（AD）是一种与认知异常相关的神经退行性疾病。AD的发生和发展受遗传和环境因素影响。铝（Al）是一种神经毒性剂，可引起氧化应激，而氧化应激与AD的进展有关。此外，Nrf2/HO-1、APOE4/LRP1、Wnt3/β-连环蛋白和TLR4/NLRP3是参与AD发病机制的主要信号通路。几种植物化学物质有望延缓AD的发展。

目的

本研究旨在研究桑色素（MOR）、百里香酚（TML）和百里醌（TMQ）等植物化学物质对氯化铝（AlCl）诱导的AD大鼠模型身体和精神活动（PhM）的神经保护作用。另一个目的是通过分子对接确定植物化学物质对AD信号通路的特异性。

方法

将80只雄性达利大鼠分为8组。每组接受：生理盐水（对照组）、AlCl（ALAD）、PhM，单独或与MOR、TML和/或TMQ联合使用，持续5周。然后对动物进行行为评估。使用脑组织进行组织病理学和生化分析，以确定神经退行性变的程度。还研究了植物化学物质对AlCl诱导的氧化应激以及AD进展中主要信号通路的影响。

结果

AlCl导致大鼠空间学习和记忆能力下降，以及大脑组织病理学变化。植物化学物质与PhM联合使用可恢复抗氧化活性，提高HO-1和Nrf2水平，阻断炎性小体激活、细胞凋亡、TLR4表达、淀粉样蛋白-β生成和tau过度磷酸化。它们还使ApoE4和LRP1水平恢复正常，并调节Wnt3/β-连环蛋白/GSK3β信号通路。