Pimaradienoic Acid Inhibits Carrageenan-Induced Inflammatory Leukocyte Recruitment and Edema in Mice: Inhibition of Oxidative Stress, Nitric Oxide and Cytokine Production.

Sandra S Mizokami,Rubia Casagrande,Ana C Zarpelon,Rodrigo C S Veneziani,Miriam S N Hohmann,Larissa Staurengo-Ferrari,Nilton S Arakawa,Maria I Possebon,Anderson R De Souza,Waldiceu A Verri,Thacyana T Carvalho,Bernhard Ryffel

doi:10.1371/journal.pone.0149656

Sandra S Mizokami, Rubia Casagrande + Show 10 more

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https://doi.org/10.1371/journal.pone.0149656

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Abstract

Pimaradienoic acid (PA; ent-pimara-8(14),15-dien-19-oic acid) is a pimarane diterpene found in plants such as Vigueira arenaria Baker (Asteraceae) in the Brazilian savannas. Although there is evidence on the analgesic and in vitro inhibition of inflammatory signaling pathways, and paw edema by PA, its anti-inflammatory effect deserves further investigation. Thus, the objective of present study was to investigate the anti-inflammatory effect of PA in carrageenan-induced peritoneal and paw inflammation in mice. Firstly, we assessed the effect of PA in carrageenan-induced leukocyte recruitment in the peritoneal cavity and paw edema and myeloperoxidase activity. Next, we investigated the mechanisms involved in the anti-inflammatory effect of PA. The effect of PA on carrageenan-induced oxidative stress in the paw skin and peritoneal cavity was assessed. We also tested the effect of PA on nitric oxide, superoxide anion, and inflammatory cytokine production in the peritoneal cavity. PA inhibited carrageenan-induced recruitment of total leukocytes and neutrophils to the peritoneal cavity in a dose-dependent manner. PA also inhibited carrageenan-induced paw edema and myeloperoxidase activity in the paw skin. The anti-inflammatory mechanism of PA depended on maintaining paw skin antioxidant activity as observed by the levels of reduced glutathione, ability to scavenge the ABTS cation and reduce iron as well as by the inhibition of superoxide anion and nitric oxide production in the peritoneal cavity. Furthermore, PA inhibited carrageenan-induced peritoneal production of inflammatory cytokines TNF-α and IL-1β. PA presents prominent anti-inflammatory effect in carrageenan-induced inflammation by reducing oxidative stress, nitric oxide, and cytokine production. Therefore, it seems to be a promising anti-inflammatory molecule that merits further investigation.

Highlights

Inflammation is a common mechanism of many diseases
Mice received per oral (p.o.) treatment with Pimaradienoic acid (PA) (Fig 1)[29] (0.1–10 mg/kg, 2% dimethyl sulfoxide (DMSO) diluted in saline) 30 minutes before intraperitoneal (i.p.) injection of carrageenan (500 μg/cavity) and the recruitment of total leukocytes, neutrophils, and mononuclear cells was assessed at 6 hours after stimulus
Mice received p.o. treatment with PA (10 mg/kg, 2% DMSO diluted in saline) 30 minutes before i.p. injection of carrageenan (500 μg/paw)

Summary

Introduction

Despite the importance of controlling inflammation, the current anti-inflammatory drugs present many side effects that limit their clinical use [1]. An important non-clinical sign of inflammation involves the recruitment of leukocytes to the inflammatory foci [2]. Cytokines activate the endothelial cells to express adhesion molecules and chemoattract leukocytes to the inflammatory foci [3]. These leukocytes are mainly neutrophils in acute inflammation. Due to the harmful effects of exacerbated inflammation, the use of anti-inflammatories is a useful clinical tool to control inflammation and reduce tissue damage [1]

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