*Article* **Nootkatone Inhibits Acute and Chronic Inflammatory Responses in Mice**

**Lindaiane Bezerra Rodrigues Dantas 1, Ana Letícia Moreira Silva 1, Cícero Pedro da Silva Júnior 2, Isabel Sousa Alcântara 2, Maria Rayane Correia de Oliveira 2,**

**Anita Oliveira Brito Pereira Bezerra Martins 2, Jaime Ribeiro-Filho 3,**

**Henrique Douglas Melo Coutinho 4, Fabíolla Rocha Santos Passos 5,**

**Lucindo José Quintans-Junior 5, Irwin Rose Alencar de Menezes 2, Ra**ff**aele Pezzani 6,7 and Sara Vitalini 8,\***


Academic Editor: Massimo Bertinaria

Received: 8 April 2020; Accepted: 5 May 2020; Published: 7 May 2020

**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 sugges<sup>t</sup> 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.

**Keywords:** nootkatone; anti-inflammatory; acute inflammation; granuloma
