Elenice M Alvarenga1, Nayara A Sousa1, Simone de Araújo1, José L P Júnior1, Alyne R Araújo2, Bruno Iles1, Dvison M Pacífico3, Gerly Anne C Brito3, Emmanuel P Souza3, Damião P Sousa4, Jand Venes R Medeiros1. 1. Laboratory of Pharmacology of Inflammation and Gastrointestinal Disorders (Lafidg), Federal University of Piauí, Parnaíba, PI, Brazil. 2. Biotechnology and Biodiversity Center Research, BIOTEC, Federal University of Piauí, Parnaíba, PI, Brazil. 3. Department of Morphology, Faculty of Medicine, Postgraduate Program in Morphofunctional Sciences, Federal University Ceará, Fortaleza, CE, Brazil. 4. Department of Pharmaceutical Sciences, Federal University of Paraíba, João Pessoa, Paraíba, Brazil.
Abstract
OBJECTIVES: We aimed to determine whether carvacryl acetate acts as a TRPA1 receptor agonist and its effects against irinotecan (CPT-11) induced intestinal mucositis in mice. METHODS: TRPA1 structure was obtained from a protein databank, and the 3D structure of carvacryl acetate was determined. Appropriate binding conformations were discovered via automatic docking simulations. To determine the effect of carvacryl acetate in vivo, mice were treated with either DMSO 2%, CPT-11, carvacryl acetate followed by CPT-11, or HC-030031, a TRPA1 antagonist, followed by carvacryl acetate. Jejunum samples were taken and structural, inflammatory and antioxidant parameters were studied. KEY FINDINGS: Eight amino acids residues in TRPA1 established stable interactions with carvacryl acetate, which led to pharmacological efficacy against CPT-11-induced intestinal mucositis via reduction of both neutropenia and bacteremia, increase in villi height and crypt depth, decrease in pro-inflammatory cytokines (interleukin-1β, keratinocyte chemoattractant and tumour necrosis factor-α) and decrease in malondialdehyde and nitric oxide metabolite levels in the jejunum. CONCLUSIONS: Carvacryl acetate is a promising anti-inflammatory and antioxidant agent, a fact confirmed through observations of its interactions with TRPA1 in CPT-11-induced intestinal mucositis in mice.
OBJECTIVES: We aimed to determine whether carvacryl acetate acts as a TRPA1 receptor agonist and its effects against irinotecan (CPT-11) induced intestinal mucositis in mice. METHODS:TRPA1 structure was obtained from a protein databank, and the 3D structure of carvacryl acetate was determined. Appropriate binding conformations were discovered via automatic docking simulations. To determine the effect of carvacryl acetate in vivo, mice were treated with either DMSO 2%, CPT-11, carvacryl acetate followed by CPT-11, or HC-030031, a TRPA1 antagonist, followed by carvacryl acetate. Jejunum samples were taken and structural, inflammatory and antioxidant parameters were studied. KEY FINDINGS: Eight amino acids residues in TRPA1 established stable interactions with carvacryl acetate, which led to pharmacological efficacy against CPT-11-induced intestinal mucositis via reduction of both neutropenia and bacteremia, increase in villi height and crypt depth, decrease in pro-inflammatory cytokines (interleukin-1β, keratinocyte chemoattractant and tumour necrosis factor-α) and decrease in malondialdehyde and nitric oxide metabolite levels in the jejunum. CONCLUSIONS:Carvacryl acetate is a promising anti-inflammatory and antioxidant agent, a fact confirmed through observations of its interactions with TRPA1 in CPT-11-induced intestinal mucositis in mice.
Authors: Harold A Silverman; Adrian Chen; Nigel L Kravatz; Sangeeta S Chavan; Eric H Chang Journal: Front Immunol Date: 2020-10-23 Impact factor: 7.561