title: Vinpocetine reduces lipopolysaccharide-induced inflammatory pain and neutrophil recruitment in mice by targeting oxidative stress, cytokines and NF-κB.
abstract: In response to lipopolysaccharide (LPS), tissue resident macrophages and recruited neutrophils produce inflammatory mediators through activation of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway. These mediators include inflammatory cytokines and reactive oxygen species that, in turn, sensitize nociceptors and lead to inflammatory pain. Vinpocetine is a nootropic drug widely used to treat cognitive and neurovascular disorders, and more recently its anti-inflammatory properties through inhibition of NF-κB activation have been described. In the present study, we used the intraplantar and intraperitoneal LPS stimulus in mice to investigate the effects of vinpocetine pre-treatment (3, 10, or 30mg/kg by gavage) in hyperalgesia, leukocyte recruitment, oxidative stress, and pro-inflammatory cytokine production (TNF-α, IL-1β, and IL-33). LPS-induced NF-κB activation and cytokine production were investigated using RAW 264.7 macrophage cell in vitro. Vinpocetine (30mg/kg) significantly reduces hyperalgesia to mechanical and thermal stimuli, and myeloperoxidase (MPO) activity (a neutrophil marker) in the plantar paw skin, and also inhibits neutrophil and mononuclear cell recruitment, superoxide anion and nitric oxide production, oxidative stress, and cytokine production (TNF-α, IL-1β and IL-33) in the peritoneal cavity. At least in part, these effects seem to be mediated by direct effects of vinpocetine on macrophages, since it inhibited the production of the same cytokines (TNF-α, IL-1β and IL-33) and the NF-κB activation in LPS-stimulated RAW 264.7 macrophages. Our results suggest that vinpocetine represents an important therapeutic approach to treat inflammation and pain induced by a gram-negative bacterial component by targeting NF-κB activation and NF-κB-related cytokine production in macrophages.
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Kenji W
authors.initials: KW
authors.lastname: Ruiz-Miyazawa
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Pinho-Ribeiro
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Larissa
authors.initials: L
authors.lastname: Staurengo-Ferrari
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes s/n, 14050-490 Ribeirão Preto, São Paulo, Brazil.
authors.forename: Rangel L
authors.initials: RL
authors.lastname: Silva
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes s/n, 14050-490 Ribeirão Preto, São Paulo, Brazil.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Alves-Filho
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes s/n, 14050-490 Ribeirão Preto, São Paulo, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes s/n, 14050-490 Ribeirão Preto, São Paulo, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Estadual de Londrina-UEL, Avenida Robert Koch, 60, Hospital Universitário, 86038-350 Londrina, Paraná, Brazil.
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.affiliation: Departamento de Ciências Patológicas, Universidade Estadual de Londrina-UEL, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx. Postal 10.011, Londrina, Paraná, Brazil. Electronic address: waldiceujr@yahoo.com.br.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009504:Neutrophils / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects*; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control*; D010529:Peritoneal Cavity; D009195:Peroxidase / Q000378:metabolism; D014748:Vinca Alkaloids / Q000494:pharmacology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014748:Vinca Alkaloids; C013983:vinpocetine; D009195:Peroxidase
keywords: Inflammation; Lipopolysaccharide; NF-κB; Oxidative stress; Pain; Vinpocetine