Advertisement

The granulopoietic cytokine granulocyte colony-stimulating factor (G-CSF) induces pain: analgesia by rutin

  • Thacyana T. Carvalho
  • Sandra S. Mizokami
  • Camila R. Ferraz
  • Marília F. Manchope
  • Sergio M. Borghi
  • Victor Fattori
  • Cassia Calixto-Campos
  • Doumit Camilios-Neto
  • Rubia Casagrande
  • Waldiceu A. VerriJr.Email author
Original Article
  • 68 Downloads

Abstract

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.

Keywords

G-CSF Flavonoids Hyperalgesia Rutin NFκB Nrf2/HO-1 

Notes

Author contributions

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.

Funding

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.

Ethical approval

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.

References

  1. 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
  2. Battiwalla M, McCarthy PL (2009) Filgrastim support in allogeneic HSCT for myeloid malignancies: a review of the role of G-CSF and the implications for current practice. Bone Marrow Transplant 43:351–356.  https://doi.org/10.1038/bmt.2008.443 CrossRefGoogle Scholar
  3. 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
  4. Borghi SM, Pinho-Ribeiro FA, Zarpelon AC, Cunha TM, Alves-Filho JC, Ferreira SH, Cunha FQ, Casagrande R, Verri WA Jr (2015) Interleukin-10 limits intense acute swimming-induced muscle mechanical hyperalgesia in mice. Exp Physiol 100:531–544.  https://doi.org/10.1113/EP085026 CrossRefGoogle Scholar
  5. 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
  6. 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
  7. 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
  8. Chung MI, Gan KH, Lin CN, Ko FN, Teng CM (1993) Antiplatelet effects and vasorelaxing action of some constitutes of Formosan plants. J Nat Prod 56:929–934.  https://doi.org/10.1021/np50096a018 CrossRefGoogle Scholar
  9. Cunha TM, Verri WA, Vivancos GG, Moreira IF, Reis S, Parada CA, Cunha FQ, Ferreira SH (2004) An electronic pressure-meter nociception paw test for mice. Braz J Med Biol Res 37:401–407.  https://doi.org/10.1590/S0100-879X2004000300018 CrossRefGoogle Scholar
  10. 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
  11. Deschner EE, Ruperto J, Wong G, Newmark HL (1991) Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis 12:1193–1196.  https://doi.org/10.1093/carcin/12.7.1193 CrossRefGoogle Scholar
  12. Devulder J, Jacobs A, Richarz U, Wiggett H (2009) Impact of opioid rescue medication for breakthrough pain on the efficacy and tolerability of long-acting opioids in patients with chronic non-malignant pain. Br J Anaesth 103:576–585.  https://doi.org/10.1093/bja/aep253 CrossRefGoogle Scholar
  13. Duarte IDG, Lorenzetti BB, Ferreira SH (1990) Peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. Eur J Pharmacol 186:289–293.  https://doi.org/10.1016/0014-2999(90)90446-D CrossRefGoogle Scholar
  14. Duarte IDG, Santos IR, Lorenzetti BB, Ferreira SH (1992) Analgesia by direct antagonism of nociceptor sensitization involves the arginine-nitric oxide-cGMP pathway. Eur J Pharmacol 217:225–227.  https://doi.org/10.1016/0014-2999(92)90881-4 CrossRefGoogle Scholar
  15. Duke JA (1992) Handbook of phytochemical constituents of GRAS herbs and other economic plants. CRC Press, Boca RatonGoogle Scholar
  16. 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
  17. Ferraz CR, Calixto-Campos C, Manchope MF, Casagrande R, Clissa PB, Baldo C, Verri WA Jr (2015) Jararhagin-induced mechanical hyperalgesia depends on TNF-α, IL-1β and NFkB in mice. Toxicon 103:119–128.  https://doi.org/10.1016/j.toxicon.2015.06.024 CrossRefGoogle Scholar
  18. Ferreira SH, Duarte ID, Lorenzetti BB (1991) The molecular mechanism of action of peripheral morphine analgesia: stimulation of the cGMP system via nitric oxide release. Eur J Pharmacol 201:121–122.  https://doi.org/10.1016/0014-2999(91)90333-L CrossRefGoogle Scholar
  19. Gerritsen ME, Williams AJ, Neish AS, Moore S, Shi Y, Collins T (1997) CREB-binding protein/p300 are transcriptional coactivators of p65. Proc Natl Acad Sci USA 94:2927.  https://doi.org/10.1073/pnas.94.7.2927 CrossRefGoogle Scholar
  20. Granados-Soto V, Flores-Murrieta FJ, Castañeda-Hernández G, López-Muñoz FJ (1995) Evidence for the involvement of nitric oxide in the antinociceptive effect of ketorolac. Eur J Pharmacol 277:281–284.  https://doi.org/10.1016/0014-2999(95)00123-3 CrossRefGoogle Scholar
  21. Guardia T, Rotelli AE, Juarez AO, Pelzer LE (2001) Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Il Farmaco 56:683–687.  https://doi.org/10.1016/S0014-827X(01)01111-9 CrossRefGoogle Scholar
  22. Haiyun D, Jianbin C, Guomei Z, Shaomin S, Jinhao P (2003) Preparation and spectral investigation on inclusion complex of β-cyclodextrin with rutin. Spectrochim Acta A Mol Biomol Spectrosc 59:3421–3429.  https://doi.org/10.1016/S1386-1425(03)00176-8 CrossRefGoogle Scholar
  23. Hernandez-Leon A, Fernández-Guasti A, González-Trujano ME (2016) Rutin antinociception involves opioidergic mechanism and descending modulation of ventrolateral periaqueductal grey matter in rats. Eur J Pain 20:274–283.  https://doi.org/10.1002/ejp.720 CrossRefGoogle Scholar
  24. Hosseinzadeh H, Nassiri-Asl M (2014) Review of the protective effects of rutin on the metabolic function as an important dietary flavonoid. J Endocrinol Investig 37:783–788.  https://doi.org/10.1007/s40618-014-0096-3 CrossRefGoogle Scholar
  25. Kociancic T, Reed MD (2003) Acetaminophen intoxication and length of treatment: how long is long enough? Pharmacotherapy 23:1052–1059.  https://doi.org/10.1592/phco.23.8.1052.32884 CrossRefGoogle Scholar
  26. 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
  27. 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
  28. Li Q, Verma IM (2002) NF-κB Regulation in the Immune System. Nat Rev Immunol 2:725–734.  https://doi.org/10.1038/nri910 CrossRefGoogle Scholar
  29. 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
  30. 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
  31. 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
  32. Pinho-Ribeiro FA, Zarpelon AC, Fattori V, Manchope MF, Mizokami SS, Casagrande R, Verri WA Jr (2016a) Naringenin reduces inflammatory pain in mice. Neuropharmacology 105:508–519.  https://doi.org/10.1016/j.neuropharm.2016.02.019 CrossRefGoogle Scholar
  33. 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
  34. 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
  35. 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
  36. Sachs D, Cunha FQ, Ferreira SH (2004) Peripheral analgesic blockade of hypernociception: activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+channel pathway. Proc Natl Acad Sci USA 101:3680–3685.  https://doi.org/10.1073/pnas.0308382101 CrossRefGoogle Scholar
  37. Sheu JR, Hsiao G, Chou PH, Shen MY, Chou DS (2004) mechanisms involved in the antiplatelet activity of rutin, a glycoside of the flavonol quercetin, in human platelets. J Agric Food Chem 52:4414–4418.  https://doi.org/10.1021/jf040059f CrossRefGoogle Scholar
  38. 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
  39. 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
  40. Tian R, Yang W, Xue Q, Gao L, Huo H, Ren D, Chen X (2016) Rutin ameliorates diabetic neuropathy by lowering plasma glucose and decreasing oxidative stress via Nrf2 signaling pathway in rats. Eur J Pharm 771:84–92.  https://doi.org/10.1016/j.ejphar.2015.12.02 CrossRefGoogle Scholar
  41. Tonussi CR, Ferreira SH (1994) Mechanism of diclofenac analgesia: direct blockade of inflammatory sensitization. Eur J Pharmacol 251:173–179.  https://doi.org/10.1016/0014-2999(94)90398-0 CrossRefGoogle Scholar
  42. Ugusman A, Zakaria Z, Chua KH, Nordin NAMM, Mahdy ZA (2014) Role of rutin on nitric oxide synthesis in human umbilical vein endothelial cells. Sci World J 2014:169370.  https://doi.org/10.1155/2014/169370 CrossRefGoogle Scholar
  43. 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
  44. Verri WA Jr, Cunha TM, Parada CA, Poole S, Cunha FQ, Ferreira SH (2006) Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development? Pharmacol Ther 112:116–138.  https://doi.org/10.1016/j.pharmthera.2006.04.001 CrossRefGoogle Scholar
  45. 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
  46. 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
  47. Wardyn JD, Ponsford AH, Sanderson CM (2015) Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways. Biochem Soc Trans 43(4):621–626.  https://doi.org/10.1042/BST20150014 CrossRefGoogle Scholar
  48. Yeligar SM, Machida K, Kalra VK (2010) Ethanol-induced HO-1 and NQO1 are differentially regulated by HIF-1alpha and Nrf2 to attenuate inflammatory cytokine expression. J Biol Chem 285:35359–35373.  https://doi.org/10.1074/jbc.M110.138636 CrossRefGoogle Scholar
  49. Yu M, Li H, Liu Q, Liu F, Tang L, Li C, Yuan Y, Zhan Y, Xu W, Li W, Chen H, Ge C, Wang J, Yang X (2011) Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. Cell Signal 23:883–892.  https://doi.org/10.1016/j.cellsig.2011.01.014 CrossRefGoogle Scholar
  50. Zhang JM, An J (2007) Cytokines, inflammation, and pain. Int Anesthesiol Clin Spring 45:27–37.  https://doi.org/10.1097/AIA.0b013e318034194e CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Thacyana T. Carvalho
    • 1
  • Sandra S. Mizokami
    • 1
  • Camila R. Ferraz
    • 1
  • Marília F. Manchope
    • 1
  • Sergio M. Borghi
    • 1
    • 2
  • Victor Fattori
    • 1
  • Cassia Calixto-Campos
    • 1
  • Doumit Camilios-Neto
    • 3
  • Rubia Casagrande
    • 4
  • Waldiceu A. VerriJr.
    • 1
    • 5
    Email author
  1. 1.Department of Pathology, Center of Biological SciencesState University of LondrinaLondrinaBrazil
  2. 2.Center for Research in Health ScienceUniversity of Northern Paraná-UNOPARLondrinaBrazil
  3. 3.Department of Biochemistry and Biotechnology, Exact Sciences CenterState University of LondrinaLondrinaBrazil
  4. 4.Department of Pharmaceutical Sciences, Center of Health SciencesState University of LondrinaLondrinaBrazil
  5. 5.Department of Pathology, Center of Biological SciencesState University of LondrinaLondrinaBrazil

Personalised recommendations