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. 2021 May 1:272:119194.
doi: 10.1016/j.lfs.2021.119194. Epub 2021 Feb 18.

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

Diva de Aguiar Magalhães  1 , Jalles Arruda Batista  1 , Stefany Guimarães Sousa  1 , Jayro Dos Santos Ferreira  2 , Lauanda da Rocha Rodrigues  2 , Cynthia Maria Carvalho Pereira  2 , José Victor do Nascimento Lima  2 , Ieda Figueira de Albuquerque  2 , Nayonara Lanara Sousa Dutra Bezerra  2 , Carlos Eduardo da Silva Monteiro  3 , Alvaro Xavier Franco  3 , Humberto Barbosa da Costa Filho  3 , Francisco Cleber Silva Ferreira  4 , Alexandre Havt  4 , David Di Lenardo  5 , Daniel Fernando Pereira Vasconcelos  6 , Jefferson Soares de Oliveira  7 , Pedro Marcos Gomes Soares  3 , André Luiz Dos Reis Barbosa  8
Affiliations

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

Diva de Aguiar Magalhães et al. Life Sci. .

Abstract

Aim: The aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis.

Material and methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Inflammation; Oxidative stress; Pirenzepine; Ulcerative colitis.

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