Carvacryl acetate, a novel semisynthetic monoterpene ester, binds to the TRPA1 receptor and is effective in attenuating irinotecan-induced intestinal mucositis in mice.

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.

• Authors: Elenice M Alvarenga, Nayara A Sousa, Simone de Araújo, José L P Júnior, Alyne R Araújo, Bruno Iles, Dvison M Pacífico, Gerly Anne C Brito, Emmanuel P Souza, Damião P Sousa, Jand Venes R Medeiros
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 69 Issue 12 Pg. 1773-1785 (Dec 2017) ISSN: 2042-7158 [Electronic] England
• PMID: 28940490 (Publication Type: Journal Article)
• Copyright: © 2017 Royal Pharmaceutical Society.

Chemical References

• Anti-Inflammatory Agents
• Antineoplastic Agents, Phytogenic
• Antioxidants
• Cytokines
• Monoterpenes
• TRPA1 Cation Channel
• Trpa1 protein, mouse
• carvacryl acetate
• Irinotecan
• Camptothecin

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (toxicity)
• Antioxidants (pharmacology)
• Bacteremia (prevention & control)
• Camptothecin (analogs & derivatives, toxicity)
• Cytokines (metabolism)
• Female
• Intestinal Mucosa (drug effects, pathology)
• Irinotecan
• Jejunum (metabolism, pathology)
• Mice
• Molecular Docking Simulation
• Monoterpenes (pharmacology)
• Mucositis (chemically induced, prevention & control)
• Neutropenia (prevention & control)
• TRPA1 Cation Channel (agonists)