A Novel 5-HT1B Receptor Agonist of Herbal Compounds and One of the Therapeutic Uses for Alzheimer's Disease

Yang Yang; Lijing Zhang; Jiaojiao Yu; Zhaobin Ma; Moxiang Li; Jin Wang; Pengcheng Hu; Jia Zou; Xueying Liu; Ying Liu; Su An; Cheng Xiang; Xiaoxi Guo; Qian Hao; Tian-Rui Xu

doi:10.3389/fphar.2021.735876

A Novel 5-HT_1B Receptor Agonist of Herbal Compounds and One of the Therapeutic Uses for Alzheimer's Disease

Front Pharmacol. 2021 Sep 6:12:735876. doi: 10.3389/fphar.2021.735876. eCollection 2021.

Authors

Yang Yang¹, Lijing Zhang¹, Jiaojiao Yu¹, Zhaobin Ma¹, Moxiang Li¹, Jin Wang¹, Pengcheng Hu¹, Jia Zou¹, Xueying Liu¹, Ying Liu¹, Su An¹, Cheng Xiang¹, Xiaoxi Guo¹, Qian Hao¹, Tian-Rui Xu¹

Affiliation

¹ Center for Pharmaceutical Sciences and Engineering, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, China.

Abstract

The serotonin receptor 5-HT_1B is widely expressed in the central nervous system and has been considered a drug target in a variety of cognitive and psychiatric disorders. The anti-inflammatory effects of 5-HT_1B agonists may present a promising approach for Alzheimer's disease (AD) treatment. Herbal antidepressants used in the treatment of AD have shown functional overlap between the active compounds and 5-HT_1B receptor stimulation. Therefore, compounds in these medicinal plants that target and stimulate 5-HT_1B deserve careful study. Molecular docking, drug affinity responsive target stability, cellular thermal shift assay, fluorescence resonance energy transfer (FRET), and extracellular regulated protein kinases (ERK) 1/2 phosphorylation tests were used to identify emodin-8-O-β-d-glucopyranoside (EG), a compound from Chinese medicinal plants with cognitive deficit attenuating and antidepressant effects, as an agonist of 5-HT_1B. EG selectively targeted 5-HT_1B and activated the 5-HT_1B-induced signaling pathway. The activated 5-HT_1B pathway suppressed tumor necrosis factor (TNF)-α levels, thereby protecting neural cells against beta-amyloid (Aβ)-induced death. Moreover, the agonist activity of EG towards 5-HT_1B receptor, in FRET and ERK1/2 phosphorylation, was antagonized by SB 224289, a 5-HT_1B antagonist. In addition, EG relieved AD symptoms in transgenic worm models. These results suggested that 5-HT_1B receptor activation by EG positively affected Aβ-related inflammatory process regulation and neural death resistance, which were reversed by antagonist SB 224289. The active compounds such as EG might act as potential therapeutic agents through targeting and stimulating 5-HT_1B receptor for AD and other serotonin-related disorders. This study describes methods for identification of 5-HT_1B agonists from herbal compounds and for evaluating agonists with biological functions, providing preliminary information on medicinal herbal pharmacology.

Keywords: 5-HT1B receptor; alzheimer’s disease; drug affinity responsive target stability; emodin-8-O-β-d-glucopyranoside; fluorescence resonance energy transfer; molecular docking.