Naringenin Inhibits Superoxide Anion-Induced Inflammatory Pain: Role of Oxidative Stress, Cytokines, Nrf-2 and the NO-cGMP-PKG-KATP Channel Signaling Pathway

Marília F Manchope; Cássia Calixto-Campos; Letícia Coelho-Silva; Ana C Zarpelon; Felipe A Pinho-Ribeiro; Sandra R Georgetti; Marcela M Baracat; Rúbia Casagrande; Waldiceu A Verri Jr

doi:10.1371/journal.pone.0153015

Naringenin Inhibits Superoxide Anion-Induced Inflammatory Pain: Role of Oxidative Stress, Cytokines, Nrf-2 and the NO-cGMP-PKG-KATP Channel Signaling Pathway

PLoS One. 2016 Apr 5;11(4):e0153015. doi: 10.1371/journal.pone.0153015. eCollection 2016.

Authors

Marília F Manchope¹, Cássia Calixto-Campos¹, Letícia Coelho-Silva¹, Ana C Zarpelon¹, Felipe A Pinho-Ribeiro¹, Sandra R Georgetti², Marcela M Baracat², Rúbia Casagrande², Waldiceu A Verri Jr¹

Affiliations

¹ Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil.
² Departamento de Ciências Farmacêuticas, Centro de Ciências de Saúde, Universidade Estadual de Londrina, Londrina, Brazil.

Abstract

In the present study, the effect and mechanism of action of the flavonoid naringenin were evaluated in superoxide anion donor (KO2)-induced inflammatory pain in mice. Naringenin reduced KO2-induced overt-pain like behavior, mechanical hyperalgesia, and thermal hyperalgesia. The analgesic effect of naringenin depended on the activation of the NO-cGMP-PKG-ATP-sensitive potassium channel (KATP) signaling pathway. Naringenin also reduced KO2-induced neutrophil recruitment (myeloperoxidase activity), tissue oxidative stress, and cytokine production. Furthermore, naringenin downregulated KO2-induced mRNA expression of gp91phox, cyclooxygenase (COX)-2, and preproendothelin-1. Besides, naringenin upregulated KO2-reduced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mRNA expression coupled with enhanced heme oxygenase (HO-1) mRNA expression. In conclusion, the present study demonstrates that the use of naringenin represents a potential therapeutic approach reducing superoxide anion-driven inflammatory pain. The antinociceptive, anti-inflammatory and antioxidant effects are mediated via activation of the NO-cGMP-PKG-KATP channel signaling involving the induction of Nrf2/HO-1 pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal
Cyclic GMP / metabolism
Cyclic GMP-Dependent Protein Kinases / metabolism
Cytokines / physiology*
Flavanones / pharmacology*
Flavanones / therapeutic use
Inflammation / drug therapy*
Inflammation / etiology
Male
Mice
NF-E2-Related Factor 2 / metabolism*
Nitric Oxide / metabolism
Oxidative Stress*
Pain / drug therapy*
Pain / etiology
Potassium Channels / metabolism
Signal Transduction*
Superoxides / metabolism*

Substances

Cytokines
Flavanones
NF-E2-Related Factor 2
Nfe2l2 protein, mouse
Potassium Channels
mitochondrial K(ATP) channel
Superoxides
Nitric Oxide
Cyclic GMP-Dependent Protein Kinases
Cyclic GMP
naringenin

Grants and funding

Regarding the authors' Funding Statement/Financial Disclosure, the authors inform that "Conselho Nacional de Desenvolvimento Científico e Teconológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Ministério da Ciências Tecnologia e Inovação (MCTI), Secretaria da Ciência, Tecnologia e Ensino Superior (SETI), Fundação Araucária and Parana State Government grants supported this study (Brazil). A.C.Z. received a postdoctoral fellowship from Fundação Araucária/CAPES (Brazil).” The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.