title: Carvacrol reduces irinotecan-induced intestinal mucositis through inhibition of inflammation and oxidative damage via TRPA1 receptor activation.
abstract: Intestinal mucositis is an inflammatory process occurring in the intestinal mucosa and is a common side effect of irinotecan hydrochloride (CPT-11) based anticancer regimens. The transient receptor potential cation channel, subfamily A, member 1 (TRPA1) receptor is highly expressed in the intestinal mucosa and has the ability to identify cell damage signaling indicates its possible association with intestinal mucositis. Carvacrol is an agonist of the TRPA1 receptor and has anti-inflammatory properties. Thus, the aim of the present study was to verify the supposed anti-inflammatory and protective action of carvacrol via TRPA1 activation against intestinal mucositis induced by CPT-11 in mice. Briefly, mice were treated with either DMSO 2% or CPT-11 (75 mg/kg, per 4 days, i.p.) or the carvacrol (25, 75 or 150 mg/kg, per 8 days, i.p.) before CPT-11. In other group, the animals were pretreated with HC-030031, a TRPA1 antagonist, 30 min before treatment with carvacrol. On day 7, animal survival and bacteremia were assessed, and following euthanasia, samples of the jejunum were obtained for morphometric analysis and measurement of antioxidant and pro-inflammatory markers. Carvacrol was found to exert an anti-inflammatory action against CPT-11-induced intestinal mucositis through strong interactions with TRPA1 receptors; reduction in the production or release or both of pro-inflammatory cytokines (TNF-α, IL-1β, and KC); and decrease in other indicators of inflammation (MPO, NF-κB, COX-2) and oxidative stress (GSH, MDA, and NOx levels). It also contributed to the restoration of the tissue architecture of the villi and crypts in the small intestine, and improved clinical parameters such as survival, body mass variation, leukogram, and blood bacterial count. Thus, TRPA1 could be a target for future therapeutic approaches in the treatment of intestinal mucositis.
authors.affiliation: Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Piauí, Parnaíba, PI, Brazil.
authors.forename: Elenice M
authors.initials: EM
authors.lastname: Alvarenga
authors.affiliation: Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Piauí, Parnaíba, PI, Brazil.
authors.forename: Luan K M
authors.initials: LK
authors.lastname: Souza
authors.affiliation: Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Piauí, Parnaíba, PI, Brazil.
authors.forename: Thiago S L
authors.initials: TS
authors.lastname: Araújo
authors.affiliation: Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Piauí, Parnaíba, PI, Brazil.
authors.forename: Kerolayne M
authors.initials: KM
authors.lastname: Nogueira
authors.affiliation: Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Piauí, Parnaíba, PI, Brazil.
authors.forename: Francisca Beatriz M
authors.initials: FB
authors.lastname: Sousa
authors.affiliation: Biotechnology and Biodiversity Center Research, BIOTEC, Federal University of Piauí, Parnaíba, PI, Brazil.
authors.forename: Alyne R
authors.initials: AR
authors.lastname: Araújo
authors.affiliation: Postgraduate Program in Morphofunctional Sciences, Department of Morphology, Faculty of Medicine, Federal University Ceará, Fortaleza, CE, Brazil.
authors.forename: Conceição S
authors.initials: CS
authors.lastname: Martins
authors.affiliation: Postgraduate Program in Morphofunctional Sciences, Department of Morphology, Faculty of Medicine, Federal University Ceará, Fortaleza, CE, Brazil.
authors.forename: Dvison M
authors.initials: DM
authors.lastname: Pacífico
authors.affiliation: Postgraduate Program in Morphofunctional Sciences, Department of Morphology, Faculty of Medicine, Federal University Ceará, Fortaleza, CE, Brazil.
authors.forename: Gerly Anne
authors.initials: GA
authors.lastname: de C Brito
authors.affiliation: Postgraduate Program in Morphofunctional Sciences, Department of Morphology, Faculty of Medicine, Federal University Ceará, Fortaleza, CE, Brazil.
authors.forename: Emmanuel P
authors.initials: EP
authors.lastname: Souza
authors.affiliation: Department of Pharmaceutical Sciences, Federal University of Paraíba, João Pessoa, Paraíba, Brazil.
authors.forename: Damião P
authors.initials: DP
authors.lastname: Sousa
authors.affiliation: Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Piauí, Parnaíba, PI, Brazil. Electronic address: jandvenes@ufpi.edu.br.
authors.forename: Jand Venes R
authors.initials: JV
authors.lastname: Medeiros
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D000081007:Cymenes; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D007422:Intestines / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D000077146:Irinotecan; D007958:Leukocyte Count; D051379:Mice; D062105:Molecular Docking Simulation; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D052016:Mucositis / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy* / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D016019:Survival Analysis; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D000081007:Cymenes; D039821:Monoterpenes; D016328:NF-kappa B; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000077146:Irinotecan; C073316:carvacrol; D009195:Peroxidase; D051546:Cyclooxygenase 2; D002166:Camptothecin
keywords: COX-2; CPT-11; Cytokines; Molecular docking; NF-κB; Oxidative stress