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

Abstract

The serotonin receptor 5-HT1B 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-HT1B 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-HT1B receptor stimulation. Therefore, compounds in these medicinal plants that target and stimulate 5-HT1B 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-HT1B. EG selectively targeted 5-HT1B and activated the 5-HT1B-induced signaling pathway. The activated 5-HT1B 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-HT1B receptor, in FRET and ERK1/2 phosphorylation, was antagonized by SB 224289, a 5-HT1B antagonist. In addition, EG relieved AD symptoms in transgenic worm models. These results suggested that 5-HT1B 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-HT1B receptor for AD and other serotonin-related disorders. This study describes methods for identification of 5-HT1B agonists from herbal compounds and for evaluating agonists with biological functions, providing preliminary information on medicinal herbal pharmacology.

Protective Effect of 20(S)-Protopanaxadiol on D-Gal-Induced Cognitively Impaired Mice Based on Its Target Protein Brain-type Creatine Kinase

“…When a small-molecule ligand binds to a protein, it can enhance the stability of the protein and prevent it from being degraded by protease, and the thermal stability of the protein can be increased, which are the principles of DARTS and CETSA, respectively. , Compared with DARTS or CETSA alone, , the combination of these two strategies makes target discovery more credible. Using the combined scheme, we previously confirmed 14-3-3 ζ and adenylate kinase 5 as targets of ginsenosides in brain tissues. ,, In addition, some studies have identified SP1 as a direct target of homoharringtonine and the 5-HT1B receptor as a target of the neuroprotective and antidepressant compound emodin-8- O -D-glucopyranoside. , …”

“…18,24,27 In addition, some studies have identified SP1 as a direct target of homoharringtonine and the 5-HT1B receptor as a target of the neuroprotective and antidepressant compound emodin-8-O-D-glucopyranoside. 38,39 To further accurately assess the physicochemical parameters of this interaction, BLI and ITC were conducted. BLI and ITC are effective tools for studying various molecular interactions in real time, and they have the advantages of small sample, consumption, non-destruction of samples and simple operation.…”

G protein-coupled Receptor Contributions to Wing Growth and Morphogenesis inDrosophila melanogaster

“…The predicted protein-protein interactions for the 5-HT1B receptor are supported by comparison with the STRING protein-protein interaction network database (Szklarczyk et al 2015(Szklarczyk et al , 2011. Unconfirmed protein-protein interactions suggest new biological insights and avenues to uncover the clinical implication of serotonin receptors with other GPCRs in a range of neurological conditions, including depression, bipolar disorder, schizophrenia, Alzheimer's disease, and cognitive function (López-Figueroa et al 2004;Yang et al 2021b;Tiger et al 2018;Garcia-Alloza et al 2004). Overall, the combined machine learning approaches for both qualitative and quantitative analyses enables a more comprehensive characterization of new regulators of epithelial morphogenesis.…”

“…Unconfirmed protein-protein interactions suggest new biological insights and avenues to uncover the clinical implication of serotonin receptors with other GPCRs in a range of neurological conditions, including depression, bipolar disorder, schizophrenia, Alzheimer’s disease, and cognitive function (López-Figueroa et al . 2004; Yang et al . 2021b; Tiger et al .…”