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

• 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
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119194

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.