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Inflammopharmacology

, Volume 26, Issue 1, pp 217–226 | Cite as

Anti-inflammatory effect of a new piperazine derivative: (4-methylpiperazin-1-yl)(1-phenyl-1H-pyrazol-4-yl)methanone

  • Daniel C. Batista
  • Daiany P. B. Silva
  • Iziara F. Florentino
  • Carina S. Cardoso
  • Merita P. Gonçalves
  • Marize C. Valadares
  • Luciano M. Lião
  • Germán Sanz
  • Boniek G. Vaz
  • Elson A. Costa
  • Ricardo MenegattiEmail author
Original Article

Abstract

Aims

This study investigates the anti-nociceptive and anti-inflammatory effects of new piperazine compound (LQFM182) as well as the toxicity acute in vitro.

Main methods

To evaluate the anti-nociceptive activity, the acetic acid-induced abdominal writhing test, tail flick test and formalin-induced pain test were used. The anti-inflammatory activity was evaluated using the models of paw oedema and pleurisy induced by carrageenan and some inflammatory parameters were evaluated, including cell migration, myeloperoxidase enzyme activity and the levels of TNF-α and IL-1β cytokines in pleural exudate. The acute oral systemic toxicity of LQFM182 in mice was evaluated through the neutral red uptake (nru) assay.

Key findings

LQFM182 (50, 100 or 200 mg/kg, p.o.) decreased the number of writhings induced by acetic acid in a dose-dependent manner, and an intermediate dose (100 mg/kg, p.o.) reduced the paw licking time of animals in the second phase of the formalin test. Furthermore, LQFM182 (100 mg/kg, p.o.) reduced oedema formation at all hours of the paw oedema induced by carrageenan test and in pleurisy test reduced cell migration from the reduction of polymorphonuclear cells, myeloperoxidase enzyme activity and the levels of pro-inflammatory cytokines IL-1β and TNF-α. Therefore, it was classified in GHS category 300 < LD50 < 2000 mg/kg.

Significance

Reduction of the TNF-α and IL-1β levels.

Keywords

Anti-inflammatory N-arylheterocycles IL-1β TNF-α 

Notes

Acknowledgements

The authors are grateful to FUNAPE/UFG, PROCAD/CAPES and CNPq for financial support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

10787_2017_390_MOESM1_ESM.doc (780 kb)
Supplementary material 1 (DOC 780 kb)

References

  1. Adami M, Coruzzi G (2014) The histamine H4 receptor: a novel target for safe anti-inflammatory drugs? Gastro Open J 1(1):7–12. doi: 10.17140/GOJ-1-103 CrossRefGoogle Scholar
  2. Ashley NT, Weil ZM, Nelson RJ (2012) Inflammation: mechanisms, costs, and natural variation. Annu Rev Ecol Evol Syst 43:385–406. doi: 10.1146/annurev-ecolsys-040212-092530 CrossRefGoogle Scholar
  3. Barrot M (2012) Tests and models of nociception and pain in rodents. Neuroscience 211:39–50. doi: 10.1016/j.neuroscience.2011.12.041 CrossRefPubMedGoogle Scholar
  4. Borenfreund E, Puerner J (1985) A simple quantitative procedure using monolayer cultures for cytotoxicity assays (HTD/NR-90). J Tissue Cult Methods 9(1):7–9. doi: 10.1007/BF01666038 CrossRefGoogle Scholar
  5. Cai W, Hu J, Li T et al (2014) Activation of histamine H4 receptors decreases epithelial-to-mesenchymal transition progress by inhibiting transforming growth factor-β1 signalling pathway in non-small cell lung cancer. Eur J Cancer 50(6):1195–1206. doi: 10.1016/j.ejca.2013.12.025 CrossRefPubMedGoogle Scholar
  6. Chae E, Yi H, Choi Y et al (2012) Synthesis and pharmacological evaluation of carbamic acid 1-phenyl-3-(4-phenyl-piperazine-1-yl)-propyl ester derivatives as new analgesic agents. Bioorg Med Chem Lett 22(7):2434–2439. doi: 10.1016/j.bmcl.2012.02.023 CrossRefPubMedGoogle Scholar
  7. Chen Y, Wang G, Xu X et al (2011a) Design, synthesis and biological activity evaluation of arylpiperazine derivatives for the treatment of neuropathic pain. Molecules 16(7):5785–5806. doi: 10.3390/molecules16075785 CrossRefPubMedGoogle Scholar
  8. Chen Y, Wang G, Xu X et al (2011b) Design, synthesis and biological activity evaluation of arylpiperazine derivatives for the treatment of neuropathic pain. Molecules 16(7):5785–5806. doi: 10.3390/molecules16075785 CrossRefPubMedGoogle Scholar
  9. Chichorro JG, Lorenzetti BB, Zampronio AR (2004) Involvement of bradykinin, cytokines, sympathetic amines and prostaglandins in formalin-induced orofacial nociception in rats. Br J Pharmacol 141(7):1175–1184. doi: 10.1038/sj.bjp.0705724 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Coruzzi G, Adami M, Guiata E et al (2007) Antiinflammatory and antinociceptive effects of the selective histamine H4-receptor antagonists JNJ7777120 and VUF6002 in a rat model of carrageenan-induced acute inflammation. Eur J Pharmacol 563(1–3):240–244. doi: 10.1016/j.ejphar.2007.02.026 CrossRefPubMedGoogle Scholar
  11. Coruzzi G, Adami M, Pozzoli C et al (2011) Selective histamine H3 and H4 receptor agonists exert opposite effects against the gastric lesions induced by HCl in the rat stomach. Eur J Pharmacol 669(1–3):121–127. doi: 10.1016/j.ejphar.2011.07.038 CrossRefPubMedGoogle Scholar
  12. Costa EA, Lino RC, Gomes MN et al (2013) Anti-inflammatory and antinociceptive activities of LQFM002—a 4-nerolidylcatechol derivative. Life Sci 92(3):237–244. doi: 10.1016/j.lfs.2012.12.003 CrossRefPubMedGoogle Scholar
  13. Cunha TM, Verri WA Jr, Silva JS et al (2005) A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc Natl Acad Sci USA 102(5):1755–1760. doi: 10.1073/pnas.0409225102 CrossRefPubMedPubMedCentralGoogle Scholar
  14. D’amour FE, Smith FL (1941) A method for determining loss of pain sensation. J Pharm Exp Ther 72:74–79Google Scholar
  15. De Oliveira CHA, Mairink LM, Pazini F et al (2013) Chemoselective and regiospecific formylation of 1-penyl-1H-pyrazoles through the duff reaction. Synth Commun 43:1633–1639. doi: 10.1080/00397911.2012.657764 CrossRefGoogle Scholar
  16. Desmarchelier C, Barros S, Repetto M et al (1997) 4-Nerolidylcatechol from Pothomorphe Spp. Scavanges Peroxyl radicals and Inhibits Fe (II)-dependent DNA damage. Planta Med 63(6):561–563. doi: 10.1055/s-2006-957767 CrossRefPubMedGoogle Scholar
  17. Di Rosa M, Giroud JP, Willoughby DA (1971) Studies on the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine. J Pathol 104(1):15–29. doi: 10.1002/path.1711040103 CrossRefPubMedGoogle Scholar
  18. Eddouks M, Chattopadhyay D, Zeggwagh NA (2012) Animal models as tools to investigate antidiabetic and anti-inflammatory plants. Evid Based Complement Alternat Med 2012:14. doi: 10.1155/2012/142087 Google Scholar
  19. Ermondi G, Boschi D, Di Stilo A et al (1998) Pyrazole analogues of prazosin. II Farmaco 53(7):519–524. doi: 10.1016/S0014-827X(98)00052-4 CrossRefGoogle Scholar
  20. Finar I, Hurlock R (1957) The preparation of some trinitrophenylpyrazoles. J Chem Soc. doi: 10.1039/JR9570003024 Google Scholar
  21. Frode TS, Souza GE, Calixto JB (2001) The modulatory role played by TNF-alpha and IL-1 beta in the inflammatory responses induced by carrageenan in the mouse model of pleurisy. Cytokine 13(3):162–168. doi: 10.1006/cyto.2000.0816 CrossRefPubMedGoogle Scholar
  22. Gupta S, Bi R, Kim C et al (2005) Role of NF-kappaB signaling pathway in increased tumor necrosis factor-alpha-induced apoptosis of lymphocytes in aged humans. Cell Death Differ 12(2):177–183. doi: 10.1038/sj.cdd.4401557 CrossRefPubMedGoogle Scholar
  23. Higgs GA, Eakins KE, Mugridge KG et al (1980) The effects of non-steroid anti-inflammatory drugs on leukocyte migration in carrageenin-induced inflammation. Eur J Pharmacol 66(1):81–86. doi: 10.1016/0014-2999(80)90297-6 CrossRefPubMedGoogle Scholar
  24. Hoesel B, Schmid JA (2013) The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer 12:86. doi: 10.1186/1476-4598-12-86 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hsieh GC, Chandran P, Salyers AK et al (2010) H4 receptor antagonism exhibits anti-nociceptive effects in inflammatory and neuropathic pain models in rats. Pharmacol Biochem Behav 95(1):41–50. doi: 10.1016/j.pbb.2009.12.004 CrossRefPubMedGoogle Scholar
  26. Hunskaar S, Hole K (1987) The formalin test in mice:dissociation between inflammatory and non-inflammatory pain. Pain 30:103–114. doi: 10.1016/0304-3959(87)90088-1 CrossRefPubMedGoogle Scholar
  27. ICCVAM (2006) Test method evaluation report (TIMER): in vitro cytotoxicity test methods for estimating starting doses for acute oral systemic toxicity test. NIH publication no. 07-4519Google Scholar
  28. Jiang W, Lim HD, Zhang M et al (2008) Cloning and pharmacological characterization of the dog histamine H4 receptor. Eur J Pharmacol 592(1–3):26–32. doi: 10.1016/j.ejphar.2008.06.095 CrossRefPubMedGoogle Scholar
  29. Kaneko H, Ye F, Ijima R et al (2014) Histamine H4 receptor as a new therapeutic target for choroidal neovascularization in age-related macular degeneration. Br J Pharmacol 171(15):3754–3763. doi: 10.1111/bph.12737 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kiss R, Keseru GM (2014) Novel histamine H4 receptor ligands and their potential therapeutic applications: an update. Expert Opin Ther Pat 24(11):1185–1197. doi: 10.1517/13543776.2014.959494 CrossRefPubMedGoogle Scholar
  31. Kiss R, Kiss B, Konczol A et al (2008) Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening. J Med Chem 51(11):3145–3153. doi: 10.1021/jm7014777 CrossRefPubMedGoogle Scholar
  32. Koster R, Anderson M, Beer ED (1959) Acetic acid for analgesic screening. Fed Proc J 18:412–418Google Scholar
  33. Liang Y, Zhou Y, Shen P (2004) NF-kappaB and its regulation on the immune system. Cell Mol Immunol 1(5):343–350PubMedGoogle Scholar
  34. Liew FY, McInnes IB (2002) The role of innate mediators in inflammatory response. Mol Immunol 38(12–13):887–890. doi: 10.1016/S0161-5890(02)00014-7 CrossRefPubMedGoogle Scholar
  35. Lima LM, Barreiro EJ (2005) Bioisosterism: a useful strategy for molecular modification and drug design. Curr Med Chem 12(1):23–49. doi: 10.2174/0929867053363540 CrossRefPubMedGoogle Scholar
  36. Malvar DC, Ferreira RT, Castro RA et al (2014) Antinociceptive, anti-inflammatory and antipyretic effects of 1.5-diphenyl-1H-Pyrazole-3-carbohydrazide, a new heterocyclic pyrazole derivative. Life Sci 95(2):81–88. doi: 10.1016/j.lfs.2013.12.005 CrossRefGoogle Scholar
  37. Mazzon E, Cuzzocrea S (2007) Role of TNF-α in lung tight junction alteration in mouse model of acute lung inflammation. Respir Res 8:75. doi: 10.1186/1465-9921-8-75 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Medina V, Croci M, Crescenti E et al (2008) The role of histamine in human mammary carcinogenesis: H3 and H4 receptors as potential therapeutic targets for breast cancer treatment. Cancer Biol Ther 7(1):28–35. doi: 10.4161/cbt.7.1.5123 CrossRefPubMedGoogle Scholar
  39. Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454(7203):428–435. doi: 10.1038/nature07201 CrossRefPubMedGoogle Scholar
  40. Mikami T, Miyasaka K (1983) Effects of several anti-inflammatory drugs on the various parameters involved in the inflammatory response in rat carrageenin-induced pleurisy. Eur J Pharmacol 95(1–2):1–12. doi: 10.1016/0014-2999(83)90261-3 CrossRefPubMedGoogle Scholar
  41. Morris CJ (2003) Carrageenan-induced paw edema in the rat and mouse. Methods Mol Biol 225:115–121. doi: 10.1385/1-59259-374-7:115 PubMedGoogle Scholar
  42. Nathan C (2002) Points of control in inflammation. Nature 420(6917):846–852. doi: 10.1038/nature01320 CrossRefPubMedGoogle Scholar
  43. Nathan C, Ding D (2010) Nonresolving inflammation. Cell 140(6):871–882. doi: 10.1016/j.cell.2010.02.029 CrossRefPubMedGoogle Scholar
  44. Nicoletti F, Auci DL, Mangano K et al (2010) 5-androstenediol ameliorates pleurisy, septic shock, and experimental autoimmune encephalomyelitis in mice. Autoimmune Dis 2010:757432. doi: 10.4061/2010/757432 PubMedPubMedCentralGoogle Scholar
  45. OECD (Organisation for Economic Cooperation and Development) (2001) Acute oral toxicity: acute toxic class method. Guideline for the testing of chemicals, n.423, http://ntp.niehs.nih.gov/iccvam/suppdocs/feddocs/oecd/oecd_gl423.pdf. Accessed 20 Nov 2014
  46. Ortiz MI (2012) Metformin and phenformin block the peripheral antinociception induced by diclofenac and indomethacin on the formalin test. Life Sci 90(1–2):8–12. doi: 10.1016/j.lfs.2011.10.009 CrossRefPubMedGoogle Scholar
  47. Parsons ME, Ganellin CR (2006) Histamine and its receptors. Br J Pharmacol 147:127–135. doi: 10.1038/sj.bjp.0706440 CrossRefGoogle Scholar
  48. Ribeiro RA, Vale ML, Thomazzi SM et al (2000) Involvement of resident macrophages and mast cells in the writhing nociceptive response induced by zymosan and acetic acid in mice. Eur J Pharmacol 387(1):111–118. doi: 10.1016/S0014-2999(99)00790-6 CrossRefPubMedGoogle Scholar
  49. Rordorf-Adam C, Geiger T, Henn R et al (1994) CGP 47969A: a novel inhibitor of the synthesis of inflammatory cytokines. Agents Actions 43(1–2):53–59CrossRefPubMedGoogle Scholar
  50. Rosland JH, Tjolsen A, Maehle B et al (1990) The formalin test in mice: effect of formalin concentration. Pain 42(2):235–242. doi: 10.1016/0304-3959(90)91167-H CrossRefPubMedGoogle Scholar
  51. Saleh TS, Calixto JB, Medeiros YS (1999) Effects of antiinflammatory drugs upon nitrate and myeloperoxidase levels in the mouse pleurisy induced by carrageenan. Peptides 20(8):949–956. doi: 10.1016/S0196-9781(99)00086-8 CrossRefPubMedGoogle Scholar
  52. Schütze S, Wiegmann K, Machleidt T et al (1995) TNF-induced activation of NF-kappa B. Immunobiology 193(2–4):193–203. doi: 10.1016/S0171-2985(11)80543-7 CrossRefPubMedGoogle Scholar
  53. Sedgwick AD (1995) Initiation of inflammatory response and its prevention. In: Bonta IL, Bray MA (eds) EUA: handbook of Inflammation. Elsevier, New York, p 253Google Scholar
  54. Shibata M, Ohkubo T, Takahashi H et al (1989) Modified formalin test: characteristic biphasic pain response. Pain 38(3):347–352. doi: 10.1016/0304-3959(89)90222-4 CrossRefPubMedGoogle Scholar
  55. Shriner RL, Kleider E (1943) Piperonylic acid. Org Synth 10:82–83. doi: 10.15227/orgsyn.010.0082 Google Scholar
  56. Silva DPB, Florentino IF, Oliveira LP et al (2015) Anti-nociceptive and anti-inflammatory activities of 4-[(1-phenyl-1H-pyrazol-4-yl) methyl] 1-piperazine carboxylic acid ethyl ester: a new piperazine derivative. Pharmacol Biochem Behav 137:86–92. doi: 10.1016/j.pbb.2015.08.008 CrossRefPubMedGoogle Scholar
  57. Sokal RR, Rohlf FJ (1981) Biometry: the principles and practice of statistics in biological research. EUA: W.H. Freeman and Company., New YorkGoogle Scholar
  58. Thurmond RL, Desai PJ, Dunford PJ et al (2004a) A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharm Exp Ther 309(1):404–413. doi: 10.1124/jpet.103.061754 CrossRefGoogle Scholar
  59. Thurmond RL, Desai PJ, Dunford PJ et al (2004b) A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther 309(1):404–413. doi: 10.1124/jpet.103.061754 CrossRefPubMedGoogle Scholar
  60. Tiligada E, Zampeli E, Sander K et al (2009) Histamine H3 and H4 receptors as novel drug targets. Expert Opin Investig Drugs 18(10):1519–1531. doi: 10.1517/14728220903188438 CrossRefPubMedGoogle Scholar
  61. Tjolsen A, Berge OG, Hunskaar S et al (1992) The formalin test: an evaluation of the method. Pain 51(1):5–17. doi: 10.1016/0304-3959(92)90003-T CrossRefPubMedGoogle Scholar
  62. Vieira MS, Oliveira V, Lima EM et al (2011) In vitro basal cytotoxicity assay applied to estimate acute oral systemic toxicity of grandisin and its major metabolite. Exp Toxicol Pathol 63(5):505–510. doi: 10.1016/j.etp.2010.03.012 CrossRefGoogle Scholar
  63. Vinegar R, Truax JF, Selph JL (1973) Some quantitative temporal characteristics of carrageenan-induced pleurisy in the rat. Proc Soc Exp Biol Med 143(3):711–714CrossRefPubMedGoogle Scholar
  64. Wersinger E, Gaboyard-Niay S, Travo C et al (2013) Symptomatic treatment of vestibular deficits: therapeutic potential of histamine H4 receptors. J Vestib Res 23(3):153–159. doi: 10.3233/VES-130493 PubMedGoogle Scholar
  65. Winter CA, Risley EA, Nuss GW (1962) Carrageenin-induced edema in hind paw of the rat as an assay for antiinflammatory drugs. Proc Soc Exp Biol Med 111:544–547. doi: 10.3181/00379727-111-27849 CrossRefPubMedGoogle Scholar
  66. Zakaria ZA, Abdul Ghani ZD, Nor RM et al (2006) Antinociceptive and anti-inflammatory activities of Dicranopteris linearis leaves chloroform extract in experimental animals. Yakugaku Zasshi 126(11):1197–1203. doi: 10.1248/yakushi.126.1197 CrossRefPubMedGoogle Scholar
  67. Zampeli E, Tiligada E (2009) The role of histamine H4 receptor in immune and inflammatory disorders. Br J Pharmacol 157(1):24–33. doi: 10.1111/j.1476-5381.2009.00151.x CrossRefPubMedPubMedCentralGoogle Scholar
  68. Zhao YQ, Wang HY, Yin JB et al (2017) The analgesic effects of celecoxib on the formalin-induced short- and long-term inflammatory pain. Pain Phys 20(4):E575–E584Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Daniel C. Batista
    • 1
  • Daiany P. B. Silva
    • 2
  • Iziara F. Florentino
    • 2
  • Carina S. Cardoso
    • 2
  • Merita P. Gonçalves
    • 2
  • Marize C. Valadares
    • 3
  • Luciano M. Lião
    • 4
  • Germán Sanz
    • 5
  • Boniek G. Vaz
    • 5
  • Elson A. Costa
    • 2
  • Ricardo Menegatti
    • 1
    Email author
  1. 1.Faculty of Pharmacy, Laboratory of Medicinal Pharmaceutical ChemistryFederal University of GoiásGoiâniaBrazil
  2. 2.Department of Pharmacology, ICBFederal University of GoiásGoiâniaBrazil
  3. 3.Laboratory of Pharmacology and Cell Toxicology, Faculty of PharmacyFederal University of GoiásGoiâniaBrazil
  4. 4.Chemistry InstituteFederal University of GoiasGoiâniaBrazil
  5. 5.Chemistry Institute, Laboratory of Chromatography and Mass Spectrometry-LaCEMFederal University of GoiásGoiâniaBrazil

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