The granulopoietic cytokine granulocyte colony-stimulating factor (G-CSF) induces pain: analgesia by rutin
- 48 Downloads
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 (KATP) 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 (NFκB), 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–KATP channel signaling activation, inhibition of NFκB 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.
KeywordsG-CSF Flavonoids Hyperalgesia Rutin NFκB Nrf2/HO-1
RC and WAV contributed with funding acquisition, supervision and study design. TTC, SSM, CRF, MFM, SMB, VF, and CC-C conducted the experiments. TTC, SSM, CRF, MFM, SMB, VF, and CC-C analyzed data. DC-N contributed with funding acquisition, supervision, review and editing. TTC, RC, and WAV wrote the paper. All authors read and approved the final version of the manuscript.
This work was supported by Fundo de Apoio ao Ensino Pesquisa e Extensão/Universidade Estadual de Londrina [FAEPE/UEL 01/2009], Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—[Finance Code 001], Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-Brazil), Ministério da Ciência, Tecnologia e Inovação (MCTI), Secretaria da Ciência, Tecnologia e Ensino Superior (SETI), Fundação Araucária and Governo do Estado do Paraná. SMB received a post-doctoral fellowship [CNPq process: 435357/2016-6].
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Animal care and manipulation were carried out following the experimental guidelines from the International Association for Study of Pain (IASP), EU Directive 2010/63/EU, and the Brazilian Council on Animal Experimentation (CONCEA). All experiments with animals in the present study were conducted according to the protocols approved by the process registered under the number 11654.2015.81, dated from October 8th, 2015 of the Ethics Committee on Animal Use of the State University of Londrina (CEUA-UEL).
Research involving human participants and/or animals
This article does not contain any studies with human participants performed by any of the authors.
- Azevedo MI, Pereira AF, Nogueira RB, Rolim FE, Brito GA, Wong DV, Lima-Júnior RC, de Albuquerque Ribeiro R, Vale ML (2013) The antioxidant effects of the flavonoids rutin and quercetin inhibit oxaliplatin-induced chronic painful peripheral neuropathy. Mol Pain 9:1–14. https://doi.org/10.1186/1744-8069-9-53 CrossRefGoogle Scholar
- Bertozzi MM, Rossaneis AC, Fattori V, Longhi-Balbinot DT, Freitas A, Cunha FQ, Alves-Filho JC, Cunha TM, Casagrande R, Verri WA Jr (2017) Diosmin reduces chronic constriction injury-induced neuropathic pain in mice. Chem Biol Interact 273:180–189. https://doi.org/10.1016/j.cbi.2017.06.014 CrossRefGoogle Scholar
- Calixto-Campos C, Carvalho TT, Hohmann MSN, Pinho-Ribeiro FA, Fattori V, Manchope MF, Zarpelon AC, Baracat MM, Georgetti SR, Casagrande R, Verri WA Jr (2015) Vanillic acid inhibits inflammatory pain by inhibiting neutrophil recruitment, oxidative stress, cytokine production, and NFκB activation in mice. J Nat Prod 78:1799–1808. https://doi.org/10.1021/acs.jnatprod.5b00246 CrossRefGoogle Scholar
- Carvalho TT, Flauzino T, Otaguiri ES, Batistela AP, Zarpelon AC, Cunha TM, Ferreira SH, Cunha FQ, Verri WA Jr (2011) Granulocyte-colony stimulating factor (G-CSF) induces mechanical hyperalgesia via spinal activation of MAP kinases and PI3K in mice. Pharmacol Biochem Behav 98:188–195. https://doi.org/10.1016/j.pbb.2010.12.027 CrossRefGoogle Scholar
- Carvalho TT, Borghi SM, Pinho-Ribeiro FA, Mizokami SS, Cunha TM, Ferreira SH, Cunha FQ, Casagrande R, Verri WA Jr (2015) Granulocyte-colony stimulating factor (G-CSF)-induced mechanical hyperalgesia in mice: role for peripheral TNFα, IL-1β and IL-10. Eur J Pharmacol 749:62–72. https://doi.org/10.1016/j.ejphar.2014.12.023 CrossRefGoogle Scholar
- Cunha TM, Roman-Campos D, Lotufo CM, Duarte HL, Souza GR, Verri WA, Funez MI, Dias QM, Schivo IR, Domingues AC, Sachs D, Chiavegatto S, Teixeira MM, Hothersall JS, Cruz JS, Cunha FQ, Ferreira SH (2010) Morphine peripheral analgesia depends on activation of the PI3 Kγ/AKT/nNOS/NO/KATP signaling pathway. PNAS 107:4442–4447. https://doi.org/10.1073/pnas.0914733107 CrossRefGoogle Scholar
- Duke JA (1992) Handbook of phytochemical constituents of GRAS herbs and other economic plants. CRC Press, Boca RatonGoogle Scholar
- Feng L, Wang D, He J, Qi D (2014) Protective effect of rutin against lipopolysaccharide-induced acute lung injury in mice. Nan Fang Yi Ke Da Xue Xue Bao 34:1282–1285Google Scholar
- Lapa FR, Gadotti VM, Missau FC, Pizzolatti MG, Marques MC, Dafré AL, Farina M, Rodrigues AL, Santos AR (2009) Antinociceptive properties of the hydroalcoholic extract and the flavonoid rutin obtained from Polygala paniculata L. in mice. Basic Clin Pharmacol Toxicol 104:306–315. https://doi.org/10.1111/j.1742-7843.2008.00365 CrossRefGoogle Scholar
- Lee DF, Kuo HP, Liu M, Chou CK, Xia W, Du Y, Shen J, Chen CT, Huo L, Hsu MC, Li CW, Ding Q, Liao TL, Lai CC, Lin AC, Chang YH, Tsai SF, Li LY, Hung MC (2009) KEAP1 E3 ligase-mediated downregulation of NF-kappaB signaling by targeting IKKbeta. Mol Cell 36:131–140. https://doi.org/10.1016/j.molcel.2009.07.025 CrossRefGoogle Scholar
- Manchope MF, Calixto-Campos C, Coelho-Silva L, Zarpelon AC, Pinho-Ribeiro FA, Georgetti SR, Baracat MM, Casagrande R, Verri WA Jr (2016) 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 11:e0153015. https://doi.org/10.1371/journal.pone.0153015 CrossRefGoogle Scholar
- Mizokami SS, Arakawa NS, Ambrosio SR, Zarpelon AC, Casagrande R, Cunha TM, Ferreira SH, Cunha FQ, Verri WA Jr (2012) Kaurenoic acid from Sphagneticola trilobata inhibits inflammatory pain: effect on cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway. J Nat Prod 75:896–904. https://doi.org/10.1021/np200989t CrossRefGoogle Scholar
- Neupogen® [Filgrastim] Package Insert Kirin-Amgen (2013) Thousand Oaks, CA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103353s5157lbl.pdf. Accessed 26 Jul 2018
- Pinho-Ribeiro FA, Fattori V, Zarpelon AC, Borghi SM, Staurengo-Ferrari L, Carvalho TT, Alves-Filho JC, Cunha FQ, Cunha TM, Casagrande R, Verri WA Jr (2016b) Pyrrolidine dithiocarbamate inhibits superoxide anion-induced pain and inflammation in the paw skin and spinal cord by targeting NF-κB and oxidative stress. Inflammopharmacology 24:97–107. https://doi.org/10.1007/s10787-016-0266-3 CrossRefGoogle Scholar
- Possebon MI, Mizokami SS, Carvalho TT, Zarpelon AC, Hohmann MSN, Staurengo-Ferrari L, Ferraz CR, Hayashida TH, de Souza AR, Ambrosio SR, Arakawa NS, Casagrande R, Verri WA Jr (2014) Pimaradienoic acid inhibits inflammatory pain: inhibition of NF-kappaB activation and cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway. J Nat Prod 77:2488–2496. https://doi.org/10.1021/np500563b CrossRefGoogle Scholar
- Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, Yamamoto M, Petrache I, Tuder RM, Biswal S (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Investig 114:1248–1259. https://doi.org/10.1172/JCI200421146 CrossRefGoogle Scholar
- So H, Kim H, Kim Y, Kim E, Pae HO, Chung HT, Kim HJ, Kwon KB, Lee KM, Lee HY, Moon SK, Park R (2008) Evidence that cisplatin-induced auditory damage is attenuated by downregulation of pro-inflammatory cytokines via Nrf2/HO-1. J Assoc Res Otolaryngol 9:290–306. https://doi.org/10.1007/s10162-008-0126-y CrossRefGoogle Scholar
- Staurengo-Ferrari L, Badaro-Garcia S, Hohmann MSN, Manchope MF, Zaninelli TH, Casagrande R, Verri WA Jr (2019) Contribution of Nrf2 modulation to the mechanism of action of analgesic and anti-inflammatory drugs in pre-clinical and clinical stages. Front Pharmacol 11(9):1536. https://doi.org/10.3389/fphar.2018.01536 CrossRefGoogle Scholar
- Valerio DA, Cunha TM, Arakawa NS, Lemos HP, Da Costa FB, Parada CA, Ferreira SH, Cunha FQ, Verri WA Jr (2007) Anti-inflammatory and analgesic effects of the sesquiterpene lactone budlein A in mice: inhibition of cytokine production dependent mechanism. Eur J Pharmacol 562:155–163. https://doi.org/10.1016/j.ejphar.2007.01.029 CrossRefGoogle Scholar
- Verri WA Jr, Souto FO, Vieira SM, Almeida SC, Fukada SY, Xu D, Alves-Filho JC, Cunha TM, Guerrero AT, Mattos-Guimaraes RB, Oliveira FR, Teixeira MM, Silva JS, McInnes IB, Ferreira SH, Louzada-Junior P, Liew FY, Cunha FQ (2010) IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy. Ann Rheum Dis 69:1697–1703. https://doi.org/10.1136/ard.2009.122655 CrossRefGoogle Scholar
- Verri WA Jr, Vicentini FTMC, Baracat MM, Georgetti SR, Cardoso RDR, Cunha TM, Ferreira SH, Cunha FQ, Fonseca MJV, Casagrande R (2012) Flavonoids as anti-inflammatory and analgesic drugs: mechanisms of action and perspectives in the development of pharmaceutical forms. In: Atta-ur-Rahman (ed) Studies in natural products chemistry. Elsevier, Amsterdam, pp 297–322. https://doi.org/10.1016/B978-0-444-53836-9.00026-8 Google Scholar