Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice.

Lindaiane Bezerra Rodrigues Dantas,Raffaele Pezzani,Henrique Douglas Melo Coutinho,Isabel Sousa Alcântara,Ana Letícia Moreira Silva,Cícero Pedro Da Silva Júnior,Sara Vitalini,Maria Rayane Correia De Oliveira,Fabíolla Rocha Santos Passos,Jaime Ribeiro-Filho,Anita Oliveira Brito Pereira Bezerra Martins,Irwin Rose Alencar De Menezes,Lucindo José Quintans-Junior

doi:10.3390/molecules25092181

Abstract

Nootkatone (NTK) is a sesquiterpenoid found in essential oils of many species of Citrus (Rutaceae). Considering previous reports demonstrating that NTK inhibited inflammatory signaling pathways, this study aimed to investigate the effects of this compound in mice models of acute and chronic inflammation. Murine models of paw edema induced by carrageenan, dextran, histamine, and arachidonic acid, as well as carrageenan-induced peritonitis and pleurisy, were used to evaluate the effects of NTK on acute inflammation. A murine model of granuloma induced by cotton pellets was used to access the impact of NTK treatment on chronic inflammation. In the acute inflammation models, NTK demonstrated antiedematogenic effects and inhibited leukocyte recruitment, which was associated with decreased vascular permeability, inhibition of myeloperoxidase (MPO), interleukin (IL)1-β, and tumor necrosis factor (TNF)-α production. In silico analysis suggest that NTZ anti-inflammatory effects may also occur due to inhibition of cyclooxygenase (COX)-2 activity and antagonism of the histamine receptor type 1 (H1). These mechanisms might have contributed to the reduction of granuloma weight and protein concentration in the homogenates, observed in the chronic inflammation model. In conclusion, NTK exerted anti-inflammatory effects that are associated with inhibition of IL1-β and TNF-α production, possibly due to inhibition of COX-2 activity and antagonism of the H1 receptor. However, further studies are required to characterize the effects of this compound on chronic inflammation.

Highlights

Inflammation is the body’s response against tissue damage triggered by a variety of endogenous and exogenous stimuli
The present study demonstrated the anti-inflammatory effects of NTK, an aromatic sesquiterpenoid widely found in the plant kingdom
A screening evaluating the effect of different doses of this compound on paw edema induced by carrageenan or dextran, demonstrated significant antiedematogenic effects at 10, 100, or 300 mg/kg in mice

Summary

Introduction

Inflammation is the body’s response against tissue damage triggered by a variety of endogenous and exogenous stimuli. The inflammatory reaction involves a series of tissue changes, such as vasodilation with increased blood flow, increased vascular permeability with plasma exudation and protein extravasation, and recruitment of leukocytes in response to cytokines and chemokines In this context, neutrophils and macrophages, which play critical roles in the early phase of inflammation, contribute to the development of many chronic inflammatory diseases [1,2]. Inflammatory mediators include a great diversity of lipids (e.g., eicosanoids), proteins (e.g., cytokines, chemokines, and adhesion molecules) and other chemically related substances that orchestrate various cellular and tissue changes through binding to receptors on leukocytes, endothelial cells, and many other cell types [3]. Persistence of the stimulus, as well as continuous production of inflammatory mediators, cause significant tissue damage, which is associated with morphological and functional changes observed in the pathogenesis of several chronic diseases [6]

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