Raghuvanshi Rinky, Nuthakki Vijay K, Singh Lovedeep, Singh Bikarma, Bharate Sonali S, Bhatti Rajbir, Bharate Sandip B
Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad-201002, India.
Natural Products & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India.
Phytomedicine. 2021 Oct;91:153659. doi: 10.1016/j.phymed.2021.153659. Epub 2021 Jul 21.
Alzheimer's disease (AD) is a complex neurodegenerative disease with no availability of disease-modifying therapeutics. The complex etiology and recent failures in clinical trials indicate the need for multitargeted agents.
The present study aims to discover new plant-based multitargeted anti-AD leads.
A library of plant extracts was screened for inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1). The secondary metabolites of active extracts were also tested, followed by enzyme-kinetics and molecular modeling to understand the mechanism of inhibition. The most active extract was investigated for in-vivo anti-dementia activity in behavioral mice models.
Among the library of 105 extracts, Woodfordia fruticosa (SBE-80) and Bergenia ciliata (SBE-65) extracts displayed significant inhibition of all three enzymes. Gallic acid, one of the constituents of both plants, shows moderate inhibition of AChE and BACE-1. Catechin-3-O-gallate (CG), another constituent of SBE-65, inhibits EeAChE, rHuAChE, and eqBChE with IC's of 29.9, 1.77, and 8.4 µM, respectively; along with a mild-inhibition of BACE-1. Ellagic acid, the constituent of SBE-80, inhibits BACE-1 with an IC value of 16 µM. The W. fruticosa extract SBE-80 at the dose of 25 mg/kg QD × 9 (PO) displayed memory-enhancing activity in Morris Water Maze and Passive Avoidance Test in Swiss albino mice. Treatment with SBE-80 also inhibits AChE in-vivo; whereas, a non-significant decrease in the serum TBARS was observed.
W. fruticosa is identified for the first time as an anti-AD lead candidate. The in-vitro and in-vivo data presented herein and the documented safety profile of W. fruticosa indicate its strong potential for preclinical development as a botanical drug for dementia/AD.
阿尔茨海默病（AD）是一种复杂的神经退行性疾病，目前尚无改变疾病进程的治疗方法。其复杂的病因以及近期临床试验的失败表明需要多靶点药物。
本研究旨在发现新的基于植物的多靶点抗AD先导化合物。
对植物提取物文库进行筛选，以检测其对乙酰胆碱酯酶（AChE）、丁酰胆碱酯酶（BChE）和β-淀粉样前体蛋白裂解酶1（BACE-1）的抑制作用。对活性提取物的次生代谢产物也进行了测试，随后进行酶动力学和分子建模以了解抑制机制。对活性最强的提取物在行为学小鼠模型中进行体内抗痴呆活性研究。
在105种提取物文库中，虾子花（SBE-80）和岩白菜（SBE-65）提取物对所有三种酶均表现出显著抑制作用。两种植物的成分之一没食子酸对AChE和BACE-1有中度抑制作用。SBE-65的另一种成分儿茶素-3-O-没食子酸（CG）对电鳗AChE（EeAChE）、重组人AChE（rHuAChE）和埃及伊蚊BChE（eqBChE）的抑制常数（IC）分别为29.9、1.77和8.4 μM；同时对BACE-1有轻度抑制作用。SBE-80的成分鞣花酸对BACE-1的抑制常数为16 μM。虾子花提取物SBE-80以25 mg/kg每日一次×9天（口服）的剂量在瑞士白化小鼠的莫里斯水迷宫和被动回避试验中表现出记忆增强活性。SBE-80治疗还能在体内抑制AChE；然而，血清丙二醛（TBARS）仅出现不显著下降。
首次鉴定出虾子花为抗AD先导候选物。本文提供的体外和体内数据以及虾子花已记录的安全性表明其作为痴呆症/AD植物药进行临床前开发的强大潜力。
