title: Pimaradienoic Acid Inhibits Carrageenan-Induced Inflammatory Leukocyte Recruitment and Edema in Mice: Inhibition of Oxidative Stress, Nitric Oxide and Cytokine Production.
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.
authors.affiliation: Departamento de Ciências Patológicas - Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Mizokami
authors.affiliation: Departamento de Ciências Patológicas - Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Miriam S N
authors.initials: MS
authors.lastname: Hohmann
authors.affiliation: Departamento de Ciências Patológicas - Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Larissa
authors.initials: L
authors.lastname: Staurengo-Ferrari
authors.affiliation: Departamento de Ciências Patológicas - Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Thacyana T
authors.initials: TT
authors.lastname: Carvalho
authors.affiliation: Departamento de Ciências Patológicas - Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.affiliation: Departamento de Ciências Farmacêuticas - Centro de Ciências de Saúde, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Possebon
authors.affiliation: Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de Franca, Franca, São Paulo, Brazil.
authors.forename: Anderson R
authors.initials: AR
authors.lastname: de Souza
authors.affiliation: Núcleo de Pesquisa em Ciências Exatas e Tecnológicas, Universidade de Franca, Franca, São Paulo, Brazil.
authors.forename: Rodrigo C S
authors.initials: RC
authors.lastname: Veneziani
authors.affiliation: Departamento de Ciências Farmacêuticas - Centro de Ciências de Saúde, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Nilton S
authors.initials: NS
authors.lastname: Arakawa
authors.affiliation: Departamento de Ciências Farmacêuticas - Centro de Ciências de Saúde, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.affiliation: Departamento de Ciências Patológicas - Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Paraná, Brazil.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D019659:Asteraceae / Q000737:chemistry*; D001938:Brazil; D002351:Carrageenan / Q000037:antagonists & inhibitors; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D016207:Cytokines / Q000096:biosynthesis*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004487:Edema; D053583:Interleukin-1beta / Q000096:biosynthesis; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects*; D010529:Peritoneal Cavity; D009195:Peroxidase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004224:Diterpenes; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C008911:pimaric acid; D002351:Carrageenan; D009195:Peroxidase