Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Digestive Diseases and Sciences
Published in: Digestive Diseases and Sciences 12/2021

01-12-2021 | Constipation | Original Article

7,8-Dihydroxyflavone Enhanced Colonic Cholinergic Contraction and Relieved Loperamide-Induced Constipation in Rats

Authors: Li Ma, Zhiqiang Qu, Luo Xu, Lei Han, Qingfang Han, Juan He, Xiao Luan, Bingxiang Wang, Yongye Sun, Baoguo He

Published in: Digestive Diseases and Sciences | Issue 12/2021

Login to get access

Abstract

Background

Whether 7,8-dihydroxyflavone (7,8-DHF), a tyrosine kinase receptor B (TrkB) agonist, modulates colonic smooth muscle motility and/or alleviates constipation has not yet been studied.

Aims

Here, we aimed to determine how 7,8-DHF influences carbachol (CCh)-stimulated contraction of colonic strips and the in vivo effect of 7,8-DHF on constipation.

Methods

Muscle strips were isolated from rat colons for recording contractile tension and performing western blotting. Constipation was induced in rats with loperamide.

Results

Although it specifically activated TrkB, 7,8-DHF applied alone neither activated PLCγ1 in the colonic strips nor induced colonic strip contraction. However, 7,8-DHF enhanced CCh-stimulated PLCγ1 activation and strip contraction. The PLCγ1 antagonist U73122 suppressed both CCh-stimulated and 7,8-DHF-enhanced/CCh-stimulated contraction. While clarifying the underlying mechanism, we revealed that 7,8-DHF augmented muscarinic M3 receptor expression in the colonic strips. The M3-selective antagonist tarafenacin specifically inhibited the 7,8-DHF-enhanced/CCh-stimulated contraction of the colonic strips. Since 7,8-DHF increased Akt phosphorylation, and LY294002 (an antagonist of PI3K upstream of Akt) dramatically inhibited both 7,8-DHF-augmented M3 expression and 7,8-DHF-enhanced/CCh-stimulated contractions, we assumed that 7,8-DHF/TrkB/Akt was associated with the modulation of M3 expression in the colonic strips. ANA-12, a specific TrkB antagonist, not only inhibited TrkB activation by 7,8-DHF but also suppressed 7,8-DHF-enhanced cholinergic contraction, 7,8-DHF/CCh-mediated activation of PLCγ1/Akt, and M3 overexpression in colonic strips. In vivo 7,8-DHF, also by promoting intestinal motility and M3 expression, significantly alleviated loperamide-induced functional constipation in rats.

Conclusions

Our results suggest that 7,8-DHF regulates colonic motility possibly via a TrkB/Akt/M3 pathway and may be applicable for alleviating constipation.
Literature
1.
Bharucha AE and Wald A. Chronic Constipation. Mayo Clin Proc. 2019. pii: S0025–6196-30123–5.
2.
Tejeda GS and Díaz-Guerra M. Integral Characterization of Defective BDNF/TrkB Signaling in Neurological and Psychiatric Disorders Leads the Way to New Therapies. Int J Mol Sci. 2017;18: E268.
3.
Waterhouse EG, Xu B. New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol Cell Neurosci. 2009;42:81–89CrossRef
4.
Chen F, Yu Y, Wang P, Dong Y, Wang T, Zuo X, Li Y. Brain-derived neurotrophic factor accelerates gut motility in slow-transit constipation. Acta Physiologica 2014;212:226–238CrossRef
5.
Chai NL, Dong L, Li ZF, Du KX, Wang JH, Yan LK, Dong XL. Effects of neurotrophins on gastrointestinal myoelectric activities of rats. World J Gastroenterol. 2003;9:1874–1877CrossRef
6.
Liu C, Chan CB, Ye K. 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders. Transl Neurodegener. 2016;6:2CrossRef
7.
Sim DY, Sohng JK, Jung HJ. Anticancer activity of 7,8-dihydroxyflavone in melanoma cells via downregulation of α-MSH/cAMP/MITF pathway. Oncol Rep. 2016;36:528–534CrossRef
8.
Chan CB, Tse MC, Liu X, Zhang S, Schmidt R, Otten R, Liu L, Ye K. Activation of muscular TrkB by its small molecular agonist 7,8-dihydroxyflavone sex-dependently regulates energy metabolism in diet-induced obese mice. Chem Biol. 2015;22:355–368CrossRef
9.
Cho SJ, Kang KA, Piao MJ et al. 7,8-Dihydroxyflavone Protects High Glucose-Damaged Neuronal Cells against Oxidative Stress. Biomol Ther (Seoul). 2019;27:85–91CrossRef
10.
Zhao J, Du J, Pan Y et al. Activation of cardiac TrkB receptor by its small molecular agonist 7,8-dihydroxyflavone inhibits doxorubicin-induced cardiotoxicity via enhancing mitochondrial oxidative phosphorylation. Free Radic Biol Med. 2019;130:557–567CrossRef
11.
Huai R, Han X, Wang B, Li C, Niu Y, Li R, Qu Z. Vasorelaxing and Antihypertensive Effects of 7,8-Dihydroxyflavone. Am J Hypert. 2014;27:750–760CrossRef
12.
He B, Qu Z, Tian Z et al. 7,8-dihydroxyflavone enhanced cholinergic contraction of rat gastric smooth muscle via augmenting muscarinic M3 receptor expression. Clin Exp Pharmacol Physiol. 2018;45:1170–1180CrossRef
13.
Ma L, Qu Z, Luan X, et al. Effects of 7,8-Dihydroxyflavone on Rat Jejunal Dynamics Subjected to Ischemia-Reperfusion Injury Clin Exp Pharmacol Physiol. 2020; 47:67–75.
14.
Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye K. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci USA 2010;107:2687–2692CrossRef
15.
Du X, Hill RA. 7,8-Dihydroxyflavone as a proneurotrophic treatment for neurodevelopmental disorders. Neurochemistry International. 2015;89:170–180CrossRef
16.
Al-Qudah M, Anderson CD, Mahavadi S, Bradley ZL, Akbarali HI, Murthy KS, Grider JR. Brain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase C. Am J Physiol Gastrointest Liver Physiol 2014;306:G328–G337CrossRef
17.
Chen F, Yu Y, Yuan X, Zuo L and Li Y. Brain-derived neurotrophic factor enhances the contraction of intestinal muscle strips induced by SP and CGRP in mice. Regul Pept. 2012;178:86–94.
18.
Luan X, Sun X, Guo F, Zhang D, Wang C, Ma L, Xu L. Lateral hypothalamic Orexin-A-ergic projections to the arcuate nucleus modulate gastric function in vivo. J Neurochem. 2017;143:697–707.
19.
Wintola OA, Sunmonu TO and Afolayan AJ. The effect of Aloe ferox Mill. in the treatment of loperamide-induced constipation in Wistar rats. BMC Gastroenterol. 2010; 10:95.
20.
Zholos AV. Regulation of TRP-like muscarinic cation current in gastrointestinal smooth muscle with special reference to PLC/InsP3/Ca2+ system. Acta Pharmacologica Sinica 2006;27:833–842CrossRef
21.
Tobin G, Giglio D, Lundgren O. Muscarinic receptor subtypes in the alimentary tract. J Physiol Pharmacol. 2009;60:3–21PubMed
22.
Harrington AM, Peck CJ, Liu L, Burcher E, Hutson JM and Southwell BR. Localization of muscarinic receptors M1R, M2R and M3R in the human colon. Neurogastroenterol Motil. 2010; 22:999–1008, e262–3.
23.
Bhattacharya S, Mahavadi S, Al-Shboul O, Rajagopal S, Grider JR, Murthy KS. Differential regulation of muscarinic M2 and M3 receptor signaling in gastrointestinal smooth muscle by caveolin-1. Am J Physiol Cell Physiol 2013;305:C334–C347CrossRef
24.
Zenko D, Hislop JN. Regulation and trafficking of muscarinic acetylcholine receptors. Neuropharmacology. 2018;136:374–382CrossRef
25.
Wang B, Li C, Huai R, Qu Z. Overexpression of ANO1/TMEM16A, an arterial Ca2+-activated Cl- channel, contributes to spontaneous hypertension. J Mol Cell Cardiol 2015;82:22–32CrossRef
26.
Ehlert FJ, Pak KJ, Griffin MT. Muscarinic agonists and antagonists: effects on gastrointestinal function. Handb Exp Pharmacol 2012;208:343–374CrossRef
27.
Sheffler DJ, Williams R, Bridges TM, Xiang Z, Kane AS, Byun NE, Jadhav S, Mock MM, Zheng F, Lewis LM, Jones CK, Niswender CM, Weaver CD, Lindsley CW, Conn PJ. A novel selective muscarinic acetylcholine receptor subtype 1 antagonist reduced seizures without impairing hippocampus-dependent learning. Mol Pharmacol. 2009;76:356–368CrossRef
28.
Gitler MS, Boulay SF, Sood VK, McPherson DW, Knap FF Jr, Zeeberg BR, Reba RC. Characterization of in vivo brain muscarinic acetylcholine receptor subtype selectivity by competition studies against (R, S)-[125I]IQNB. Brain Res. 1995;687:71–78CrossRef
29.
Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK, Haga T, Kobayashi T. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature. 2012;482:547–551CrossRef
30.
Salcedo C, Davalillo S, Cabellos J, Lagunas C, Balsa D, Pérez-Del-Pulgar S, Ballarín M, Fernández A. In vivo and in vitro pharmacological characterization of SVT-40776, a novel M3 muscarinic receptor antagonist, for the treatment of overactive bladder. Br J Pharmacol. 2009;156:807–817CrossRef
31.
Hanauer SB. The role of loperamide in gastrointestinal disorders. Rev Gastroenterol Disord. 2008;8:15–20PubMed
32.
Coulie B, Szarka LA, Camilleri M, Burton DD, McKinzie S, Stambler N, Cedarbaum JM. Recombinant human neurotrophic factors accelerate colonic transit and relieve constipation in humans. Gastroenterology 2000;119:41–50CrossRef
33.
Liu X, Obianyo O, Chan CB, Huang J, Xue S, Yang JJ, Zeng F, Goodman M, Ye K. Biochemical and Biophysical Investigation of the Brain-derived Neurotrophic Factor Mimetic 7,8-Dihydroxyflavone in the Binding and Activation of the TrkB Receptor. J Bio Chem 2014;289:27571–27584CrossRef
Metadata
Title
7,8-Dihydroxyflavone Enhanced Colonic Cholinergic Contraction and Relieved Loperamide-Induced Constipation in Rats
Authors
Li Ma
Zhiqiang Qu
Luo Xu
Lei Han
Qingfang Han
Juan He
Xiao Luan
Bingxiang Wang
Yongye Sun
Baoguo He
Publication date
01-12-2021
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 12/2021
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-020-06817-y

Other articles of this Issue 12/2021

Digestive Diseases and Sciences 12/2021 Go to the issue

Original Article

Development and Validation of an Easy-to-Use Risk Scoring System for Screening High-Risk Varices in Patients with HBV-Related Compensated Advanced Chronic Liver Disease

Original Article

Mesenteric Lymph Duct Ligation Alleviates Acute Lung Injury Caused by Severe Acute Pancreatitis Through Inhibition of High Mobility Group Box 1-Induced Inflammation in Rats

Original Article

Utility of Endoscopy in Hospitalized Patients with Gastrointestinal Hemorrhage and Pulmonary Hypertension

Original Article

Perception of Illness and Its Association with Treatment Willingness in Patients with Newly Diagnosed Nonalcoholic Fatty Liver Disease

Original Article

Curcumin Chemoprevention Reduces the Incidence of Braf Mutant Colorectal Cancer in a Preclinical Study

Original Article

Long-Term Dietary Changes in Subjects with Glucose Galactose Malabsorption Secondary to Biallelic Mutations of SLC5A1
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits