淫羊藿、黄芪、葛根有效组分复方对阿尔茨海默病脑铁超载的干预作用及其机制研究

The increased brain iron deposition has been found in Alzheimer disease (AD) patients, which might be the result of misregulation of brain metal transporters, increasing oxidative stress and inflammatory factors, imbalance of peripheral iron metabolism, and multiple system organ failure. Dysregulation of brain iron homeostasis is central to early neuropathological events in AD, including oxidative stress, inflammatory processes, amyloid deposition, tau phosphorylation, and neuronal cell cycle regulatory failure, and leading to apoptosis. Therefore, brain iron deposition has been proposed to play an important role in the pathophysiology of AD. Thus, the concept of iron chelation holds considerable promise as a therapeutic strategy for AD pathogenesis. A single-blind, 2-year clinical study with the prototype iron chelator desferrioxamine (DFO) showed that sustained intramuscular administration slowed the clinical progression of the dementia associated with AD. Another metal ligand, clioquinol, also ameliorated cognitive decline in AD patients. However, clioquinol is highly toxic, while the hydrophilic nature of DFO and its large molecular size limit absorption across the gastrointestinal tract and prevent it from penetrating the blood-brain barrier (BBB). Oppositely, traditional chinese medicines are characterized by security, nontoxic, brain-permeable, and multifunction, which can overcome the pharmaco-clinical limitations of iron chelator. The beneficial effects of Epimedium, Astragalus, Radix Puerariae have been attributed to the presence of active compounds that are powerful anti-oxidants, anti-inflammatory, and regulation of of each organ function. Therefore, it is believed that active compounds of Epimedium, Astragalus, Radix Puerariae may protect against brain iron overload and attenuate memory deficits. Therefore, the present study will evaluate the therapeutic effect of the active compounds of Epimedium, Astragalus, Radix Puerariae on the neuropathology, deficits of spatial learning and memory, brain iron deposition in amyloid precursor protein (APP) -transgenic (Tg) AD mice, and further experiments will be performed to study the molecular mechanisms. The aim of our study is to reveal novel therapeutic targets for neurodegenerative disorders.

研究发现阿尔茨海默病（Alzheimer's disease，AD）患者的脑铁水平异常升高。AD患者脑铁含量增高可能与某些脑组织铁代谢相关蛋白表达失控，脑内自由基及炎症因子异常升高，外周铁代谢失衡及脏腑功能衰退相关。异常增高的脑铁启动机体级联放大机制，最终导致神经元死亡，在AD的发生发展中发挥重要作用。应用DFO等铁螯合剂均显著缓解了AD患者的病情发展，但这些化学药物都有一定毒副作用或口服困难等缺点，而从中药淫羊藿、黄芪、葛根提取的有效组分具有调节脏腑功能，清除自由基，降低炎症反应等多重功效，可以从多个方面抑制AD脑铁超载，缓解铁超载带来的中枢神经系统功能衰退。因此，本课题以转基因AD模型小鼠为观察对象，运用行为学、免疫组化和分子生物学等技术研究淫羊藿、黄芪、葛根有效组分复方对AD模型小鼠脑铁超载的干预作用及其机制，为开发治疗AD的新药提供新的思路和策略。

研究发现阿尔茨海默病（Alzheimer's disease，AD）患者的脑铁水平异常升高。脑铁的异常积累出现在AD初期，与Aβ沉积和NFT等神经病理损伤的形成密切相关，在AD的发生发展中发挥重要作用。应用DFO等铁螯合剂均显著缓解了AD患者的病情发展，但这些化学药物都有一定毒副作用或口服困难等缺点。中药兼有营养和药用双重作用，其作用大多为多靶点、多途径和多系统，且能透过血脑屏障，生物利用度高，不良反应轻，所以中药治疗AD的潜力十分巨大。因此，本课题以转基因AD模型小鼠为观察对象，运用行为学、免疫组化和分子生物学等技术研究淫羊藿、黄芪、葛根有效组分复方对AD模型小鼠脑铁超载的干预作用及其机制。研究结果发现，淫羊藿、黄芪、葛根有效成分复方可以有效的改善AD模型小鼠的学习记忆能力，减少AD模型小鼠大脑皮质老年斑的沉积，降低神经元的损伤。淫羊藿、黄芪、葛根有效组分复方可以减轻AD模型小鼠脑铁的沉积，其降低脑铁的机制可能包括3个方面：①通过降低神经元铁摄取相关蛋白（DMT1 with IRE、DMT1-without IRE、TRF和TfR1）的表达，升高铁释放相关蛋白（FPN1、CP及HP）的表达，减少铁摄取，增加铁释放，从而降低神经元内铁沉积；②通过增强脑SOD和GSH-Px的活性，降低脑内脂质过氧化MDA的累积，降低脑内IL-1β、IL-6、TNF等炎性因子的水平，脑内自由基生成降低或炎症因子的释放的减少，使铁蛋白（FN）释放的自由铁量减少，降低脑铁超载；③通过促进肾脏促红细胞生成素（EPO）的分泌，促进红细胞的生成，使外周铁利用增加，有效的降低AD模型小鼠血清铁蛋白（sFN）和血清铁（SI）水平，降低脑铁流入，并降低铁在肾脏、肝脏、心脏和肺脏等处的沉积，降低上述器官的氧化损伤。本项目的研究成果从一个全新的角度来阐述中药防治AD的内在机制，并为研制治疗AD的新的方药开辟一条新的思路。