McN-A-343, a muscarinic agonist, reduces inflammation and oxidative stress in an experimental model of ulcerative colitis

The aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis. After the induction of 6% acetic acid colitis, mice were treated with McN-A-343 0.5, 1.0, and 1.5 mg/kg or dexamethasone (DEXA, 2.0...

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Bibliographic Details
Published in:Life sciences (1973) 2021-05, Vol.272, p.119194-119194, Article 119194
Main Authors: Magalhães, Diva de Aguiar, Batista, Jalles Arruda, Sousa, Stefany Guimarães, Ferreira, Jayro dos Santos, da Rocha Rodrigues, Lauanda, Pereira, Cynthia Maria Carvalho, do Nascimento Lima, José Victor, de Albuquerque, Ieda Figueira, Bezerra, Nayonara Lanara Sousa Dutra, Monteiro, Carlos Eduardo da Silva, Franco, Alvaro Xavier, da Costa Filho, Humberto Barbosa, Ferreira, Francisco Cleber Silva, Havt, Alexandre, Di Lenardo, David, Vasconcelos, Daniel Fernando Pereira, de Oliveira, Jefferson Soares, Soares, Pedro Marcos Gomes, Barbosa, André Luiz dos Reis
Format: Article
Language:English
Subjects:
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride - metabolism
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride - pharmacology
Acetic acid
Acetylcholine receptors (muscarinic)
Agonists
Animals
Colitis - drug therapy
Colitis - metabolism
Colitis, Ulcerative - drug therapy
Colitis, Ulcerative - metabolism
Colon - metabolism
Cyclooxygenase 2 - metabolism
Cyclooxygenase-2
Cytokines
Cytokines - metabolism
Dexamethasone
Dexamethasone - pharmacology
Disease Models, Animal
Dual energy X-ray absorptiometry
Gene expression
Glutathione
Glutathione - metabolism
Inflammation
Inflammation - pathology
Inflammation Mediators - metabolism
Inflammatory bowel disease
Inflammatory bowel diseases
Inflammatory response
Interleukin 1
Interleukin-1beta - metabolism
Intestine
Male
Malondialdehyde
Malondialdehyde - metabolism
Mice
Muscarinic Agonists - pharmacology
NF-kappa B - metabolism
NF-κB protein
Nitrogen dioxide
Oxidative stress
Oxidative Stress - drug effects
Peroxidase
Pirenzepine
Receptor, Muscarinic M1
Stress concentration
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-TNF
Tumor necrosis factor-α
Ulcerative colitis
Weight
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Summary:The aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis. After the induction of 6% acetic acid colitis, mice were treated with McN-A-343 0.5, 1.0, and 1.5 mg/kg or dexamethasone (DEXA, 2.0 mg/kg) or pirenzepine (PIR, 10 mg/kg; M1 mAChR antagonist). Colonic inflammation was assessed by macroscopic and microscopic lesion scores, colonic wet weight, myeloperoxidase (MPO) activity, interleukin-1 beta (IL1-β) levels and tumor necrosis factor alpha (TNF-α), glutathione (GSH), malondialdehyde (MDA) and nitrate and nitrite (NO3/NO2), mRNA expression of IKKα, nuclear factor kappa beta (NF-kB) and cyclooxygenase-2 (COX-2), as well protein expression of NF-kB and COX-2. Treatment with McN-A-343 at a concentration of 1.5 mg/kg showed a significant reduction in intestinal damage as well as a decrease in wet weight, MPO activity, pro-inflammatory cytokine concentration, markers of oxidative stress and expression of inflammatory mediators. The action of the M1 agonist by the administration of pirenzepine, which promoted the blocking of the mAChR M1-mediated anti-inflammatory response, has also been proven. The results suggest that peripheral colonic M1 mAChR is involved in reversing the pro-inflammatory effect of experimentally induced colitis, which may represent a promising therapeutic alternative for patients with ulcerative colitis.
ISSN:0024-3205
1879-0631
DOI:10.1016/j.lfs.2021.119194