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

Magalhães, Diva de Aguiar; Batista, Jalles Arruda; Sousa, Stefany Guimarães; Ferreira, Jayro dos Santos; Rodrigues, Lauanda da Rocha; Pereira, Cynthia Maria Carvalho; Lima, José Victor do Nascimento; Albuquerque, Ieda Figueira de; Bezerra, Nayonara Lanara Sousa Dutra; Monteiro, Carlos Eduardo da Silva; Franco, Álvaro Xavier; Filho, Humberto Barbosa da Costa; Ferreira, Francisco Cleber Silva; Havt, Alexandre; Lenardo, David Di; Oliveira, Jefferson Soares de; Soares, Pedro Marcos Gomes; Barbosa, André Luiz dos Reis

doi:10.1016/j.lfs.2021.119194

Cited by 7 publications

(4 citation statements)

References 61 publications

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“…Future experiments will seek a deeper mechanistic understanding of precisely how M 1 Rs regulate cell proliferation, if this requires proximity between M 1 R and M 3 R as was reported for other plasma membrane G protein-coupled receptors with reciprocal relationships [45], and whether a similar reciprocal relationship exists between M 1 R and M 3 R activation in other gastrointestinal cancers-current evidence suggests this is highly likely. Lastly, animal studies are required to demonstrate both the efficacy and safety of M 1 R agonism in models of both sporadic and colitis-associated colon cancer; a report that McN-A-343 treatment reduces inflammation and oxidative stress in a murine model of ulcerative colitis suggests promise for the latter indication [46].…”

Section: Discussionmentioning

confidence: 99%

Selective Activation of M1 Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation

Sundel,

Sampaio Moura,

Cheng

et al. 2023

Cancers

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M3 muscarinic receptor (M3R) activation stimulates colon cancer cell proliferation, migration, and invasion; M3R expression is augmented in colon cancer and ablating M3R expression in mice attenuates colon neoplasia. Several lines of investigation suggest that in contrast to these pro-neoplastic effects of M3R, M1R plays an opposite role, protecting colon epithelial cells against neoplastic transformation. To pursue these intriguing findings, we examined the relative expression of M1R versus M3R in progressive stages of colon neoplasia and the effect of treating colon cancer cells with selective M1R agonists. We detected divergent expression of M1R and M3R in progressive colon neoplasia, from aberrant crypt foci to adenomas, primary colon cancers, and colon cancer metastases. Treating three human colon cancer cell lines with two selective M1R agonists, we found that in contrast to the effects of M3R activation, selective activation of M1R reversibly inhibited cell proliferation. Moreover, these effects were diminished by pre-incubating cells with a selective M1R inhibitor. Mechanistic insights were gained using selective chemical inhibitors of post-muscarinic receptor signaling molecules and immunoblotting to demonstrate M1R-dependent changes in the activation (phosphorylation) of key downstream kinases, EGFR, ERK1/2, and p38 MAPK. We did not detect a role for drug toxicity, cellular senescence, or apoptosis in mediating M1R agonist-induced attenuated cell proliferation. Lastly, adding M1R-selective agonists to colon cancer cells augmented the anti-proliferative effects of conventional chemotherapeutic agents. Collectively, these results suggest that selective M1R agonism for advanced colon cancer, alone or in combination with conventional chemotherapy, is a therapeutic strategy worth exploring.

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Section: Discussionmentioning

confidence: 99%

Selective Activation of M1 Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation

Sundel,

Sampaio Moura,

Cheng

et al. 2023

Cancers

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“…Notably, DSS-induced colitis was more severe in M 3 KO mice [ 23 ]. Recently, McN-A-343 was reported to exhibit anti-inflammatory effects in acetic acid-treated mice, another experimental model of ulcerative colitis [ 62 ]. McN-A-343 is widely used as an M1 selective agonist owing to its relatively high efficacy against the M1 subtype; however, it also acts on other mAChR subtypes [ 63 ].…”

Section: Role Of Machrs In the Epithelial Barrier Against Inflammator...mentioning

confidence: 99%

Role of Muscarinic Acetylcholine Receptors in Intestinal Epithelial Homeostasis: Insights for the Treatment of Inflammatory Bowel Disease

Uwada

Nakazawa

Muramatsu

et al. 2023

IJMS

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Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is an intestinal disorder that causes prolonged inflammation of the gastrointestinal tract. Currently, the etiology of IBD is not fully understood and treatments are insufficient to completely cure the disease. In addition to absorbing essential nutrients, intestinal epithelial cells prevent the entry of foreign antigens (micro-organisms and undigested food) through mucus secretion and epithelial barrier formation. Disruption of the intestinal epithelial homeostasis exacerbates inflammation. Thus, the maintenance and reinforcement of epithelial function may have therapeutic benefits in the treatment of IBD. Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors for acetylcholine that are expressed in intestinal epithelial cells. Recent studies have revealed the role of mAChRs in the maintenance of intestinal epithelial homeostasis. The importance of non-neuronal acetylcholine in mAChR activation in epithelial cells has also been recognized. This review aimed to summarize recent advances in research on mAChRs for intestinal epithelial homeostasis and the involvement of non-neuronal acetylcholine systems, and highlight their potential as targets for IBD therapy.

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“…O receptor muscarínico M1 foi avaliado como uma via antiinflamatória intestinal em camundongos com RCU induzida por ácido acético, e sua estimulação reduziu importantes parâmetros inflamatórios. Com Isso, buscou-se avaliar a ação anti-inflamatória da EPI através desse receptor (MAGALHÃES et al, 2021).…”

Section: Introductionunclassified

“….p. ), seguindo estudo deMagalhães et al (2021). Após 18 horas da indução da retocolite os animais foram eutanasiados pelo método descrito porGuazelli et al (2013).…”

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Avaliação Da Participação Do Receptor Muscarínico M1 Na Atividade Anti-Inflamatória Da Epiisopiloturina

Rocha¹,

Costa²,

Lima³

et al. 2022

BJCR

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INTRODUÇÃO: As Doenças Inflamatórias Intestinais são um grupo de distúrbios inflamatórios crônicos que acometem o trato gastrointestinal. Neste grupo insere-se a Retocolite Ulcerativa, caracterizada pela inflamação da mucosa do cólon e reto. Suas abordagens terapêuticas objetivam reduzir danos ocasionados pelo processo inflamatório e seus sintomas, entretanto, essas terapêuticas possuem diversos efeitos adversos sendo necessário buscar medicamentos com menos efeitos secundários. A espécie Pilocarpus microphyllus do Jaborandi, é uma planta que possui diversos alcaloides com propriedades farmacológicas, entre elas a pilocarpina, um alcaloide colinérgico. Entre os resíduos industriais gerados pela sua produção encontra-se a epiisopiloturina (EPI), um alcaloide imidazólico com propriedades antiparasitárias e anti-inflamatórias. O receptor muscarínico M1 possui ação anti-inflamatória intestinal quando estimulado, e assim levantou-se a hipótese que a epiisopiloturina, estruturalmente semelhante ao agonista muscarínico pilocarpina, tenha seu mecanismo de ação por essa via. OBJETIVO: Avaliar a participação do receptor muscarínico M1 na atividade anti-inflamatória da epiisopiloturina através de parâmetros inflamatórios morfológicos. MÉTODOS: Para a avaliação da atividade anti-inflamatória da EPI, os animais receberam a substância nas doses 0,01, 0,1 e 1,0 (mg/kg, i.p.), 17 horas após a indução da retocolite ulcerativa. A avaliação do receptor muscarínico M1 na reposta anti-inflamatória da EPI foi testada pelo bloqueio da ação de epiisopiloturina com o antagonista seletivo pirenzepina (10 mg/kg, i.p.). Foram utilizados parâmetros morfológicos (peso úmido, escores macroscópicos e microscópicos de lesão) na avaliação da atividade anti-inflamatória. RESULTADOS: A EPI na dose 0,1 mg/kg foi capaz de reverter os parâmetros morfológicos de inflamação, diminuindo o peso úmido e as lesões macro e micro do tecido. Os animais que receberam epiisopiloturina juntamente com o antagonista pirenzepina apresentaram possível bloqueio dos efeitos anti-inflamatórios. CONCLUSÃO: Infere-se que a ação anti-inflamatória da epiisopiloturina se dá possivelmente pelo receptor muscarínico M1, pois, após o bloqueio deste receptor, a epiisopiloturina teve seu efeito anti-inflamatório bloqueado.

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

Cited by 7 publications

References 61 publications

Selective Activation of M1 Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation

Selective Activation of M1 Muscarinic Receptors Attenuates Human Colon Cancer Cell Proliferation

Role of Muscarinic Acetylcholine Receptors in Intestinal Epithelial Homeostasis: Insights for the Treatment of Inflammatory Bowel Disease

Avaliação Da Participação Do Receptor Muscarínico M1 Na Atividade Anti-Inflamatória Da Epiisopiloturina

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