The citrus flavonone naringenin reduces lipopolysaccharide-induced inflammatory pain and leukocyte recruitment by inhibiting NF-κB activation.
Lipopolysaccharide (LPS) is the major structural component of Gram-negative bacteria cell wall and a highly pro-inflammatory toxin. Naringenin is found in Citrus fruits and exhibits antioxidant and anti-inflammatory properties through inhibition of NF-κB activation but its effects in LPS-induced inflammatory pain and leukocyte recruitment were not investigated yet. We investigated the effects of naringenin in mechanical hyperalgesia, thermal hyperalgesia and leukocyte recruitment induced by intraplantar injection of LPS in mice. We found that naringenin reduced hyperalgesia to mechanical and thermal stimuli, myeloperoxidase (MPO, a neutrophil and macrophage marker) and N-acetyl-β-D-glucosaminidase (NAG, a macrophage marker) activities, oxidative stress and cytokine (TNF-α, IL-1β, IL-6, and IL-12) production in the paw skin. In the peritoneal cavity, naringenin reduced neutrophil and mononuclear cell recruitment, and abrogated MPO and NAG activity, cytokine and superoxide anion production, and lipid peroxidation. In vitro, pre-treatment with naringenin inhibited superoxide anion and cytokine (TNF-α, IL-1β, IL-6, and IL-12) production by LPS-stimulated RAW 264.7 macrophages. Finally, we demonstrated that naringenin inhibited NF-κB activation in vitro and in vivo. Therefore, naringenin is a promising compound to treat LPS-induced inflammatory pain and leukocyte recruitment.
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx., Postal 10.011, Londrina, Paraná, Brazil.
Felipe A
FA
Pinho-Ribeiro
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx., Postal 10.011, Londrina, Paraná, Brazil.
Ana C
AC
Zarpelon
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx., Postal 10.011, Londrina, Paraná, Brazil.
Sandra S
SS
Mizokami
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx., Postal 10.011, Londrina, Paraná, Brazil.
Sergio M
SM
Borghi
Carlos Chagas Institute/Fiocruz, Rua Professor Algacyr Munhoz Mader, 3775, 81350-010, Curitiba, Brazil.
Juliano
J
Bordignon
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 14050-490 Ribeirão Preto, São Paulo, Brazil.
Rangel L
RL
Silva
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 14050-490 Ribeirão Preto, São Paulo, Brazil.
Thiago M
TM
Cunha
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 14050-490 Ribeirão Preto, São Paulo, Brazil.
Jose C
JC
Alves-Filho
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 14050-490 Ribeirão Preto, São Paulo, Brazil.
Fernando Q
FQ
Cunha
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Estadual de Londrina, Avenida Robert Koch, 60, Hospital Universitário, 86038-350 Londrina, Paraná, Brazil.
Rubia
R
Casagrande
Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid, Km 380, PR445, 86057-970, Cx., Postal 10.011, Londrina, Paraná, Brazil. Electronic address: waverri@uel.br.
Waldiceu A
WA
Verri
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D019587:Dietary Supplements; D044950:Flavanones / Q000378:metabolism / Q000627:therapeutic use*; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D000067996:RAW 264.7 Cells; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013314:Stress, Mechanical; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D015415:Biomarkers; D044950:Flavanones; D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C005273:naringenin
Cytokines; Inflammatory pain; Leukocyte recruitment; NF-κB; Oxidative stress