期刊
INFLAMMOPHARMACOLOGY
卷 27, 期 6, 页码 1285-1296出版社
SPRINGER BASEL AG
DOI: 10.1007/s10787-019-00591-8
关键词
G-CSF; Flavonoids; Hyperalgesia; Rutin; NF kappa B; Nrf2; HO-1
资金
- Fundo de Apoio ao Ensino Pesquisa e Extensao/Universidade Estadual de Londrina [FAEPE/UEL 01/2009]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior-Brasil (CAPES) [001]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq-Brazil)
- Ministerio da Ciencia, Tecnologia e Inovacao (MCTI)
- Secretaria da Ciencia, Tecnologia e Ensino Superior (SETI)
- Fundacao Araucaria
- Governo do Estado do Parana
- CNPq [435357/2016-6]
Rutin is a glycone form of the flavonol quercetin and it reduces inflammatory pain in animal models. Therapy with granulocyte colony-stimulating factor (G-CSF) is known by the pain caused as its main side effect. The effect of rutin and its mechanisms of action were evaluated in a model of hyperalgesia induced by G-CSF in mice. The mechanical hyperalgesia induced by G-CSF was reduced by treatment with rutin in a dose-dependent manner. Treatment with both rutin + morphine or rutin + indomethacin, at doses that are ineffectual per se, significantly reduced the pain caused by G-CSF. The nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG)-ATP-sensitive potassium channel (K-ATP) signaling pathway activation is one of the analgesic mechanisms of rutin. Rutin also reduced the pro-hyperalgesic and increased anti-hyperalgesic cytokine production induced by G-CSF. Furthermore, rutin inhibited the activation of the nuclear factor kappa-light-chain enhancer of activated B cells (NF kappa B), which might explain the inhibition of the cytokine production. Treatment with rutin upregulated the decreased mRNA expression of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) combined with enhancement of the mRNA expression of the Nrf2 downstream target heme oxygenase (HO-1). Intraperitoneal (i.p.) treatment with rutin did not alter the mobilization of neutrophils induced by G-CSF. The analgesia by rutin can be explained by: NO-cGMP-PKG-K-ATP channel signaling activation, inhibition of NF kappa B and triggering the Nrf2/HO-1 pathway. The present study demonstrates rutin as a promising pharmacological approach to treat the pain induced by G-CSF without impairing its primary therapeutic benefit of mobilizing hematopoietic progenitor cells into the blood.
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