RESUMEN
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-1ß, 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.
Asunto(s)
Antiinflamatorios/farmacología , Camptotecina/análogos & derivados , Monoterpenos/farmacología , Mucositis/prevención & control , Animales , Antineoplásicos Fitogénicos/toxicidad , Antioxidantes/farmacología , Bacteriemia/prevención & control , Camptotecina/toxicidad , Citocinas/metabolismo , Femenino , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Irinotecán , Yeyuno/metabolismo , Yeyuno/patología , Ratones , Simulación del Acoplamiento Molecular , Mucositis/inducido químicamente , Neutropenia/prevención & control , Canal Catiónico TRPA1/agonistasRESUMEN
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-1ß, 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.