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CC BY 4.0 · Arq Neuropsiquiatr 2022; 80(09): 900-907
DOI: 10.1055/s-0042-1755321
Original Article

Bioflavonoid exerts analgesic and anti-inflammatory effects via transient receptor potential 1 channel in a rat model

Bioflavonoide exerce efeitos analgésicos e anti-inflamatórios via canal receptor do potencial transitório 1 em um modelo de rato
Mohammad Mahdi Zarei 
1   Islamic Azad University, Department of Pharmacology, Karaj, Iran.
,
Zohreh Abdolmaleki 
1   Islamic Azad University, Department of Pharmacology, Karaj, Iran.
,
Siamak Shahidi 
2   University of Medical Sciences, School of Medicine, Department of Physiology, Hamadan, Iran.
3   Hamadan University of Medical Sciences, Neurophysiology Research Center, Hamadan, Iran.
› Author Affiliations Support This research was supported by a grant (No. 1397–115) from the Faculty of Veterinary Medicine, Karaj Branch, Islamic Azad University, Iran.
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Abstract

Background Pain is an uncomfortable sensation in the body. Kaempferol is a flavonoid with antinociceptive effects. Transient receptor potential (TRP) channels have been characterized in the sensory system.

Objective This study evaluated the central antinociceptive effect of Kaempferol and possible mechanisms of action of transient receptor potential cation channel subfamily V member 1 (TRPV1).

Methods Capsaicin as a TRPV agonist (5 μg/μL, intracerebroventricular [ICV]) and capsazepine as its antagonist (10 μg/μL, icv) were used to test the analgesic effect of kaempferol (1.5 mg, ICV). Morphine (10 μg, ICV) was used as a positive control. The other groups were treated with a combination of kaempferol and capsaicin, kaempferol and capsazepine, and capsaicin and capsazepine. The cannula was implanted in the cerebroventricular area. The tail-flick, acetic acid, and formalin tests were used to assess analgesic activity. For evaluation of antiinflammatory effect, the formalin-induced rat paw edema was used.

Results Kaempferol significantly decreased pain in the acute pain models, including the tail-flick and the first phase of the formalin test. In the late phase of the formalin test, as a valid model of nociception, capsazepine inhibited the antinociceptive effect of kaempferol.

Conclusions Kaempferol has an analgesic effect in the acute pain model and can affect inflammatory pain. Also, the TRPV1 channel plays a role in the antinociceptive activity of kaempferol.

Resumo

Antecedentes A dor é uma sensação desconfortável no corpo. Kaempferol é um flavonoide com efeitos antinociceptivos. Canais receptores de potencial transitório têm sido caracterizados no sistema sensorial.

Objetivo Este estudo avaliou o efeito antinociceptivo central do kaempferol e os possíveis mecanismos de ação do TRPV1.

Métodos Capsaicina como agonista de TRPV (5 μg/μL, intracerebroventricular [ICV]) e capsazepina como seu antagonista (10 μg/μL, icv) foram usados para testar o efeito analgésico do kaempferol (1,5 mg, ICV). A morfina (10 μg, ICV) foi usada como controle positivo. Os outros grupos foram tratados com uma combinação de kaempferol e capsaicina, kaempferol e capsazepina e capsaicina e capsazepina. A cânula foi implantada na área cerebroventricular. Os testes de movimento de cauda, ácido acético e formalina foram usados para avaliar a atividade analgésica. Para avaliação do efeito anti-inflamatório, foi utilizado o edema de pata de rato induzido por formalina.

Resultados Kaempferol diminuiu significativamente a dor nos modelos de dor aguda, incluindo o movimento da cauda e a primeira fase do teste de formalina. Na fase tardia do teste da formalina, como modelo válido de nocicepção, a capsazepina inibiu o efeito antinociceptivo do kaempferol.

Conclusões Kaempferol tem efeito analgésico no modelo de dor aguda e pode afetar a dor inflamatória. Além disso, o canal TRPV1 desempenha um papel na atividade antinociceptiva do kaempferol.

Keywords

Analgesia - TRPA1 Cation Channel - Rats - Flavonoids

Palavras-chave

Analgesia - Canal de cátion TRPA1 - Ratos - Flavonoides

Authors' Contributions

All authors: study concept and design, analysis and interpretation of data, and critical revision of the manuscript for important intellectual content; MMZZA: acquisition of data, statistical analysis, and drafting of the manuscript; SS: administrative, technical, and material support; ZA: study supervision.




Publication History

Received: 28 September 2021

Accepted: 26 December 2021

Article published online:
09 November 2022

© 2022. Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Huang T, Lin S-H, Malewicz NM. et al. Identifying the pathways required for coping behaviours associated with sustained pain. Nature 2019; 565 (7737): 86-90
    CrossrefPubMedGoogle Scholar
  • 2 Dahlhamer J, Lucas J, Zelaya C. et al. Prevalence of chronic pain and high-impact chronic pain among adults - united states, 2016. MMWR Morb Mortal Wkly Rep 2018; 67 (36) 1001-1006 DOI: 10.15585/mmwr.mm6736a2.
    CrossrefPubMedGoogle Scholar
  • 3 Carter GT, Duong V, Ho S, Ngo KC, Greer CL, Weeks DL. Side effects of commonly prescribed analgesic medications. Phys Med Rehabil Clin N Am 2014; 25 (02) 457-470
    CrossrefPubMedGoogle Scholar
  • 4 Fallahzadeh A, Mohammadi S. An investigation of the antinociceptive and anti-inflammatory effects of hydroalcoholic extract of inula helenium on male rats. Majallah-i Danishgah-i Ulum-i Pizishki-i Babul 2016; 18 (12) 57-63
    Google Scholar
  • 5 Golshani Y, Zarei M, Mohammadi S. Acute/chronic pain relief: Is althaea officinalis essential oil effective. Avicenna J Neuro Psych Physiol 2015
    Google Scholar
  • 6 Imran M, Rauf A, Shah ZA. et al. Chemo-preventive and therapeutic effect of the dietary flavonoid kaempferol: A comprehensive review. Phytother Res 2019; 33 (02) 263-275
    CrossrefPubMedGoogle Scholar
  • 7 Cho HJ, Park JH. Kaempferol induces cell cycle arrest in ht-29 human colon cancer cells. J Cancer Prev 2013; 18 (03) 257-263 DOI: 10.15430/jcp.2013.18.3.257.
    CrossrefPubMedGoogle Scholar
  • 8 El-Kott AF, Bin-Meferij MM, Eleawa SM, Alshehri MM. Kaempferol protects against cadmium chloride-induced memory loss and hippocampal apoptosis by increased intracellular glutathione stores and activation of pten/ampk induced inhibition of akt/mtor signaling. Neurochem Res 2020; 45 (02) 295-309 DOI: 10.1007/s11064-019-02911-4.
    CrossrefPubMedGoogle Scholar
  • 9 Abo-Salem OM. Kaempferol attenuates the development of diabetic neuropathic pain in mice: Possible anti-inflammatory and anti-oxidant mechanisms. Maced J Med Sci 2014; 7 (03) 424-430
    CrossrefGoogle Scholar
  • 10 Kishore L, Kaur N, Singh R. Effect of Kaempferol isolated from seeds of Eruca sativa on changes of pain sensitivity in Streptozotocin-induced diabetic neuropathy. Inflammopharmacology 2018; 26 (04) 993-1003
    CrossrefPubMedGoogle Scholar
  • 11 Jian T, Chen J, Ding X. et al. Flavonoids isolated from loquat (Eriobotrya japonica) leaves inhibit oxidative stress and inflammation induced by cigarette smoke in COPD mice: the role of TRPV1 signaling pathways. Food Funct 2020; 11 (04) 3516-3526
    CrossrefPubMedGoogle Scholar
  • 12 Szallasi A. Vanilloid (capsaicin) receptors in health and disease. Am J Clin Pathol 2002; 118 (01) 110-121 DOI: 10.1309/7ayy-vvh1-gqt5-j4r2.
    CrossrefPubMedGoogle Scholar
  • 13 Frias B, Merighi A. Capsaicin, nociception and pain. Molecules 2016; 21 (06) E797 DOI: 10.3390/molecules21060797.
    CrossrefPubMedGoogle Scholar
  • 14 Jara-Oseguera A, Simon SA, Rosenbaum T. TRPV1: on the road to pain relief. Curr Mol Pharmacol 2008; 1 (03) 255-269 DOI: 10.2174/1874467210801030255.
    CrossrefPubMedGoogle Scholar
  • 15 Cui M, Gosu V, Basith S, Hong S, Choi S. Polymodal transient receptor potential vanilloid type 1 nocisensor: Structure, modulators, and therapeutic applications. Adv Protein Chem Struct Biol 2016; 104: 81-125 DOI: 10.1016/bs.apcsb.2015.11.005.
    CrossrefPubMedGoogle Scholar
  • 16 Hara K, Haranishi Y, Terada T, Takahashi Y, Nakamura M, Sata T. Effects of intrathecal and intracerebroventricular administration of luteolin in a rat neuropathic pain model. Pharmacol Biochem Behav 2014; 125: 78-84 DOI: 10.1016/j.pbb.2014.08.011.
    CrossrefPubMedGoogle Scholar
  • 17 Cohen-Pfeffer JL, Gururangan S, Lester T. et al. Intracerebroventricular delivery as a safe, long-term route of drug administration. Pediatr Neurol 2017; 67: 23-35 DOI: 10.1016/j.pediatrneurol.2016.10.022.
    CrossrefPubMedGoogle Scholar
  • 18 Slavc I, Cohen-Pfeffer JL, Gururangan S. et al. Best practices for the use of intracerebroventricular drug delivery devices. Mol Genet Metab 2018; 124 (03) 184-188 DOI: 10.1016/j.ymgme.2018.05.003.
    CrossrefPubMedGoogle Scholar
  • 19 Paxinos G. Watson c1998 the rat brain in stereotaxic coordinates. Academic, San Diego.
    Google Scholar
  • 20 Christoph T, Grünweller A, Mika J. et al. Silencing of vanilloid receptor TRPV1 by RNAi reduces neuropathic and visceral pain in vivo. Biochem Biophys Res Commun 2006; 350 (01) 238-243
    CrossrefPubMedGoogle Scholar
  • 21 Mahmoodi M, Mohammadi S, Zarei M. Antinociceptive effect of hydroalcoholic leaf extract of tribulus terrestris l. In male rat. Majallah-i Danishgah-i Ulum-i Pizishki-i Babul 2013; 15 (06) 36-43
    Google Scholar
  • 22 Zhou Q, Bao Y, Zhang X. et al. Optimal interval for hot water immersion tail-flick test in rats. Acta Neuropsychiatr 2014; 26 (04) 218-222
    CrossrefPubMedGoogle Scholar
  • 23 McGaraughty S, Chu KL, Bitner RS. et al. Capsaicin infused into the PAG affects rat tail flick responses to noxious heat and alters neuronal firing in the RVM. J Neurophysiol 2003; 90 (04) 2702-2710
    CrossrefPubMedGoogle Scholar
  • 24 Negus SS, Vanderah TW, Brandt MR, Bilsky EJ, Becerra L, Borsook D. Preclinical assessment of candidate analgesic drugs: recent advances and future challenges. J Pharmacol Exp Ther 2006; 319 (02) 507-514
    CrossrefPubMedGoogle Scholar
  • 25 Asgari Neamatian M, Yaghmaei P, Mohammadi S. Assessment of the antinociceptive, antiinflammatory and acute toxicity effects of ducrosia anethifolia essential oil in mice. Majallah-i Ilmi-i Danishgah-i Ulum-i Pizishki-i Kurdistan 2017; 22 (03) 74-84
    Google Scholar
  • 26 Tanideh N, Nematollahi SL, Hosseini SV. et al. The healing effect of hypericum perforatum extract on acetic acid-induced ulcerative colitis in rat. Ann Colorect Res 2014;2(04):
    Google Scholar
  • 27 Kang DR, Belal SA, Choe HS, Shin DK, Shim KS. Effect of kaempferol on cyclooxygenase 2 (cox2) and cytosolic phospholipase a2 (cpla2) protein expression in balb/c mice. Iran J Allergy Asthma Immunol 2018; 17 (05) 428-435
    CrossrefPubMedGoogle Scholar
  • 28 Lee KM, Lee KW, Jung SK. et al. Kaempferol inhibits UVB-induced COX-2 expression by suppressing Src kinase activity. Biochem Pharmacol 2010; 80 (12) 2042-2049 DOI: 10.1016/j.bcp.2010.06.042.
    CrossrefPubMedGoogle Scholar
  • 29 Hu WH, Dai DK, Zheng BZ. et al. The binding of kaempferol-3-O-rutinoside to vascular endothelial growth factor potentiates anti-inflammatory efficiencies in lipopolysaccharide-treated mouse macrophage RAW264.7 cells. Phytomedicine 2021; 80: 153400 DOI: 10.1016/j.phymed.2020.153400.
    CrossrefPubMedGoogle Scholar
  • 30 García-Mediavilla V, Crespo I, Collado PS. et al. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol 2007; 557 (2-3): 221-229 DOI: 10.1016/j.ejphar.2006.11.014.
    CrossrefPubMedGoogle Scholar
  • 31 Cobzaru A. High-concentration capsaicin patch (qutenza)-a new step in treatment of neuropathic pain. Amaltea Medical, Editura Magister; 2012
    Google Scholar
  • 32 Tjølsen A, Berge O-G, Hunskaar S, Rosland JH, Hole K. The formalin test: an evaluation of the method. Pain 1992; 51 (01) 5-17
    CrossrefPubMedGoogle Scholar
  • 33 Zarei M, Mohammadi S, Komaki A. Antinociceptive activity of Inula britannica L. and patuletin: In vivo and possible mechanisms studies. J Ethnopharmacol 2018; 219: 351-358
    CrossrefPubMedGoogle Scholar
  • 34 Lopes DM, Cater HL, Thakur M, Wells S, McMahon SB. A refinement to the formalin test in mice. F1000 Res 2019; 8: 891-901 DOI: 10.12688/f1000research.18338.2.
    CrossrefPubMedGoogle Scholar
  • 35 Fischer M, Carli G, Raboisson P, Reeh P. The interphase of the formalin test. Pain 2014; 155 (03) 511-521 DOI: 10.1016/j.pain.2013.11.015.
    CrossrefPubMedGoogle Scholar
  • 36 Komatsu T, Katsuyama S, Takano F. et al. Possible involvement of the μ opioid receptor in the antinociception induced by sinomenine on formalin-induced nociceptive behavior in mice. Neurosci Lett 2019; 699: 103-108 DOI: 10.1016/j.neulet.2019.01.035.
    CrossrefPubMedGoogle Scholar
  • 37 Verma PR, Joharapurkar AA, Chatpalliwar VA, Asnani AJ. Antinociceptive activity of alcoholic extract of Hemidesmus indicus R.Br. in mice. J Ethnopharmacol 2005; 102 (02) 298-301
    CrossrefPubMedGoogle Scholar
  • 38 Woodman OL, Chan ECh. Vascular and anti-oxidant actions of flavonols and flavones. Clin Exp Pharmacol Physiol 2004; 31 (11) 786-790
    CrossrefPubMedGoogle Scholar
  • 39 Zygmunt PM, Ermund A, Movahed P. et al. Monoacylglycerols activate TRPV1–a link between phospholipase C and TRPV1. PLoS One 2013; 8 (12) e81618
    CrossrefPubMedGoogle Scholar
  • 40 do Nascimento JET, de Morais SM, de Lisboa DS. et al. The orofacial antinociceptive effect of Kaempferol-3-O-rutinoside, isolated from the plant Ouratea fieldingiana, on adult zebrafish (Danio rerio). Biomed Pharmacother 2018; 107: 1030-1036
    CrossrefPubMedGoogle Scholar
  • 41 Mallet C, Barrière DA, Ermund A. et al. TRPV1 in brain is involved in acetaminophen-induced antinociception. PLoS One 2010; 5 (09) e12748
    CrossrefPubMedGoogle Scholar
  • 42 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389 (6653): 816-824
    CrossrefPubMedGoogle Scholar
  • 43 Aghazadeh Tabrizi M, Baraldi PG, Baraldi S, Gessi S, Merighi S, Borea PA. Medicinal chemistry, pharmacology, and clinical implications of trpv1 receptor antagonists. Med Res Rev 2017; 37 (04) 936-983 DOI: 10.1002/med.21427.
    CrossrefPubMedGoogle Scholar
  • 44 Pingle S, Matta J, Ahern G. Capsaicin receptor: Trpv1 a promiscuous trp channel. Transient receptor potential (trp) channels: Springer; 2007. p. 155–71.
    Google Scholar
  • 45 Liao HT, Lee HJ, Ho YC, Chiou LC. Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition. Br J Pharmacol 2011; 163 (02) 330-345
    CrossrefPubMedGoogle Scholar
  • 46 Lv S, Yang YJ, Hong S. et al. Intrathecal apelin-13 produced different actions in formalin test and tail-flick test in mice. Protein Pept Lett 2013; 20 (08) 926-931 DOI: 10.2174/0929866511320080010.
    CrossrefPubMedGoogle Scholar