FSHW | 黄曲霉神经毒性分子机制及潜在的神经保护剂

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Introduction

黄曲霉毒素（AFTs）是由农作物上的某些真菌产生的最臭名昭著的致命真菌毒素之一。黄曲霉毒素对哺乳动物具有高度毒性，已知会引起一系列有害影响，包括神经、肝、肾单位和免疫毒性。在这篇原始综述中，总结了黄曲霉毒素诱导的神经毒性机制和新型神经保护剂的临床潜力。黄曲霉毒素B1（AFB1）是已鉴定的21种黄曲霉毒素中毒性最强的同源物。最近的研究表明，通过食物接触AFB1和/或其代谢产物通常会导致动物和人类的致命神经毒性。动物研究表明，AFB1暴露可导致异常行为变化，包括焦虑、嗜睡障碍、抑郁样行为、认知、学习和记忆缺陷，以及进食行为减少。总结了现有的文献汇编，涵盖了AFB1诱导的神经毒性的异常神经行为变化和分子机制。讨论了上述抗氧化食品和益生菌补充剂对AFB1诱导的神经毒性的化学保护作用和神经保护机制。这篇综述的首要目标是提供有见地的观点，促进对AFB1诱导的神经毒性的分子机制的更多研究，更重要的是开发针对这种广泛存在的食源性毒素的神经保护剂。

AFB1诱导神经毒性的分子机制

氧化应激机制

AFB1暴露通过诱导ROS和RNS产生、上调NOX2和NF-κB/iNOS/NO途径以及下调抗氧化途径（如SOD、CAT、GPX和GSH），在脑组织中引起广泛的氧化应激（图2）。OXR1的抑制也有助于AFB1诱导的神经细胞氧化损伤。因此，补充抗氧化剂或抑制NOX2和NF-κB/iNOS/NO通路可能对AFB1诱导的氧化应激和神经毒性提供有效的神经保护作用。

炎症反应与细胞焦亡

AFB1及其代谢产物可诱导炎症反应和细胞焦亡，这可能部分涉及各种信号通路，包括NLRP3、TLR2/4、NF-κB和GSDMD信号通路。

线粒体功能失调及其凋亡通路的激活

线粒体从根本上说是细胞的“动力”和ATP的主要来源。线粒体是ROS和RNS的来源和靶点。过量的ROS或RNS产生破坏线粒体功能，最终导致能量匮乏，降低细胞活力。在神经元细胞中，线粒体是钙缓冲和ATP产生的最重要的细胞器。因此，神经元细胞对线粒体功能障碍高度敏感。据报道，大鼠反复暴露于AFB1可显著上调神经组织中 Na + /K + -ATP酶的活性，下调 Mg 2+ -ATP酶的活性；表明线粒体能量代谢是AFB1诱导的神经毒性的关键因素。AFB1诱导的神经毒性涉及线粒体功能障碍、DNA损伤和细胞凋亡，这可能部分依赖于ROS的产生、线粒体钙超载、线粒体ATP酶活性的下调和ERK/MAPK通路的激活。

抗AFB1诱导的神经毒性的神经保护剂

许多研究报道了小分子抗氧化化合物（例如槲皮素、姜黄素和没食子酸以及富马酸二甲酯），中草药提取物（如朝鲜蓟叶提取物、大白菜乙醇提取物、南瓜提取物和番红花茶）和益生菌补充剂（如双歧杆菌属和乳酸杆菌属）可以通过消除氧化应激、炎症反应、，细胞凋亡或焦性细胞死亡。

Conclusion

神经毒性是AFT暴露最有害的影响之一。长期暴露于AFB1可能导致渗透穿过血脑屏障并在脑组织中积聚。AFT神经毒性表现为神经病理学变化，如各种异常神经行为，包括抑郁、厌食、学习和记忆缺陷以及运动活动障碍。在细胞和分子水平上，AFB1诱导的神经毒性涉及多种作用机制，包括氧化应激的诱导、神经胶质细胞的激活、炎症反应、肠道菌群紊乱、神经递质的异常变化、线粒体功能障碍、细胞凋亡和焦下垂。关键信号通路涉及GSDMD、TLR2、TLR4、Akt、NF-κB、ERK/MAPK、PKC、细胞周期阻滞和线粒体凋亡通路。

鉴于上述情况，需要开发新的神经保护剂来治疗AFB1诱导的神经毒性。迄今为止，一些小分子化合物（例如槲皮素、姜黄素和没食子酸，以及富马酸二甲酯），中草药提取物（例如，朝鲜蓟叶提取物、白屈菜乙醇提取物、南瓜提取物和番红花茶）或益生菌（例如，双歧杆菌属和乳酸杆菌属）已显示出通过靶向上述信号通路作为改善AFB1诱导的神经行为异常和神经毒性的临床制剂的前景。这些令人兴奋的发现突出了前瞻性研究的几个未来方向：1）需要人体临床试验和动物试验来增强上述神经保护化合物或益生菌的神经保护作用；2）探讨AFTs暴露的环境优先级与神经毒性诱导之间的相关性—是否会加剧神经退行性疾病的发生，如多发性硬化症、帕金森病、阿尔茨海默病等；3）解读肠道微生态失调导致AFB1诱导的神经毒性的精确分子机制；4）深入研究AFB1暴露诱发抑郁症的神经化学和信号传导基础。

作者简介

代重山，男，博士，教授，研究生导师。研究方向为分子毒理学与创新药物开发，主要致力于抗菌药物、霉菌毒素及环境污染物的分子毒理学机制及中药单体的减毒增效技术研究。担任中国毒理学会兽医毒理分会委员，Evidence-Based Complementary and Alternative Medicine等SCI期刊编委，Toxics、Metabolites等SCI期刊编委。主持或参加国家自然科学基金、国家重点研发项目3项，以第一或通信作者在Cell Reports、PLoS Pathogens、Cell Death & Disease、Pharmacology & Therapeutics、Small等高水平期刊发表论文60余篇，（其中ESI高倍引2篇，F1000收录1篇），H指数30；申请或获得专利20项；曾获亚洲毒理学会、北京科协奖励10余次。

Molecular mechanisms of aflatoxin neurotoxicity and potential neuroprotective agents

Chongshan Daia,b,*, Erjie Tianc, Hui Lid, Subhajit Das Guptae, Zhihui Haoa, Zhanhui Wanga, Tony Velkovf, Jianzhong Shena,b,*

a National Key Laboratory of Veterinary Public Health and Safety, Beijing Key Laboratory of Detection Technology for Animal-Derived Food Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China

b Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China

c College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China

d Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, China

e Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75230, USA

f Monash Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Victoria 3800, Australia

*Corresponding author.

Abstract

Aflatoxins (AFTs) represent one of the most notorious classes of deadly mycotoxins produced by certain fungi that are found on agricultural crops. Aflatoxins are highly toxic to mammals and are known to cause a series of detrimental effects, including neuro-, hepato-, nephron-, and immuno-toxicity. In this original review we summarize the mechanisms of aflatoxin-induced neurotoxicity and the clinical potential of novel neuroprotective agents. Aflatoxin B1 (AFB1) is the most toxic congener among the 21 identified AFTs. Recent studies have shown that food borne exposure to AFB1 and/or its metabolites often leads to fatal neurotoxicity in animals and humans. Animal studies indicated that AFB1 exposure could induce abnormal behavioral changes, including anxiety, lethargy disorders, depression-like behavior, cognitive, learning and memory defects, and decreased feeding behavior. Mechanistically, AFB1 exposure has been associated with lipid peroxidation, ablation of non-enzymatic and enzymatic antioxidant defense systems and decreased neurotransmitter levels. AFB1 exposure has also been shown to induce DNA damage, apoptosis, pyroptosis, and mitochondrial dysfunction in the brain tissue. Several signaling pathways, including gasdermin D, toll like receptor 2 (TLR2), TLR4, Akt, NF-κB, ERK/MAPK, protein kinase C (PKC), and mitochondrial apoptotic pathways have been shown to participate in AFB1-induced neuronal or astrocyte cell death. Targeting these pathways by small molecules (e.g., quercetin, curcumin, and gallic acid, and dimethyl fumarate), Chinese herbal extracts (e.g., Artichoke leaf extract, Chelidonium majus ethanolic extract, pumpkin extract, and Crocus sativus L. tea), and probiotic supplements could effectively improve AFB1-induced neurobehavioral abnormalities and neurotoxicity. To date, the precise molecular mechanisms of AFB1-induced neurotoxicity and potential neuroprotective agents remain unclear. In the present review, the clinical manifestations, molecular mechanisms, and potential neuroprotective agents of AFB1-induced neurotoxicity are summarized in the broadest overview. It is most hopeful that this broad reaching review provides valuable insights and stimulates broader discussion to develop the effective neuroprotective agents against aflatoxins.

Reference:

DAI C S, TIAN E J, LI H, et al. Molecular mechanisms of aflatoxin neurotoxicity and potential neuroprotective agents[J]. Food Science and Human Wellness, 2024, 13(5): 2445-2455. DOI:10.26599/FSHW.2022.9250201.

本文编译内容由作者提供

编辑：梁安琪；责任编辑：孙勇

封面图片来源：图虫创意