Department of Pharmacology, Xuanwu Hospital of Capital Medical University, Beijing Geriatric Medical Research Center, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, 100053, China.
Department of Central Lab, Xuanwu Hospital of Capital Medical University, Beijing, China.
J Nat Med. 2018 Jun;72(3):596-606. doi: 10.1007/s11418-018-1177-y. Epub 2018 Mar 5.
Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. Emerging evidence indicates that there is a tight relationship between mitochondrial dysfunction and β-amyloid (Aβ) formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on Aβ production and neurotrophins in the brains of rats by using a mitochondrial dysfunction rat model induced by sodium azide (NaN), an inhibitor of mitochondrial cytochrome c oxidase (COX). NaN was administered to rats by continuous subcutaneous infusion for 28 days via implanted osmotic minipumps to establish the animal model. TSG was intragastrically administered starting 24 h after the operation. The activity of mitochondrial COX was measured by a biochemical method. The content of Aβ 1-42 was detected by ELISA. The expression of neurotrophic factors was determined by Western blot and immunohistochemistry. The results showed that NaN infusion for 28 days induced a decrease in mitochondrial COX activity, an increase in Aβ 1-42 content and the expression of amyloidogenic β-amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1) and presenilin 1 (PS1), and a decline in the expression of neurotrophins in the hippocampus of rats. Intragastrical administration of TSG elevated mitochondrial COX activity, decreased Aβ 1-42 content and the expression of APP, BACE1 and PS1, and enhanced the expression of nerve growth factor, brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of NaN-infused rats. These findings suggest that TSG may be beneficial in blocking or slowing the progression of AD by enhancing mitochondrial function, decreasing Aβ production and increasing neurotrophic factors at some extent.
阿尔茨海默病（AD）是一种不可逆的神经退行性脑疾病，其发病机制复杂。新出现的证据表明，线粒体功能障碍与β-淀粉样蛋白（Aβ）形成之间存在紧密关系。2,3,5,4'-四羟基二苯乙烯-2-O-β-D-葡萄糖苷（TSG）是从何首乌中提取的主要活性成分之一。本研究旨在通过使用线粒体细胞色素 c 氧化酶（COX）抑制剂叠氮化钠（NaN）诱导的线粒体功能障碍大鼠模型，研究 TSG 对大鼠大脑中 Aβ 产生和神经营养因子的影响。通过植入的渗透微型泵对大鼠进行持续皮下输注 NaN 28 天，以建立动物模型。术后 24 小时开始通过胃内给药给予 TSG。通过生化方法测量线粒体 COX 的活性。通过 ELISA 检测 Aβ1-42 的含量。通过 Western blot 和免疫组织化学测定神经营养因子的表达。结果显示，连续输注 NaN 28 天可导致线粒体 COX 活性降低、Aβ1-42 含量增加以及淀粉样前体蛋白（APP）、β-位 APP 裂解酶 1（BACE1）和早老素 1（PS1）的表达增加，以及大鼠海马区神经营养因子的表达下降。胃内给予 TSG 可提高线粒体 COX 活性，降低 Aβ1-42 含量和 APP、BACE1 和 PS1 的表达，并增强神经生长因子、脑源性神经营养因子（BDNF）及其受体原肌球蛋白相关激酶 B（TrkB）在 NaN 输注大鼠海马区的表达。这些发现表明，TSG 可能通过增强线粒体功能、减少 Aβ 产生和在一定程度上增加神经营养因子，从而有益于阻断或减缓 AD 的进展。
