title: Aryl-1,3,5-triazine ligands of histamine H4receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide.
abstract: OBJECTIVE
  Histamine H4receptor (H4R) offers a great potential for new therapeutic strategies for the treatment of inflammation-based diseases. The aim of this study is to present the pharmacological profile of two recently synthesized ligands of H4R with particular reference to their anti-inflammatory and analgesic activity.
  
  
  METHODS
  We used mice and rats in the in vivo tests. We also used murine RAW 264.7 cells and isolated guinea-pig ileum in in vitro test.
  
  
  METHODS
  In the in vivo tests, animals were pre-treated with the increasing doses of investigated compounds (12.5, 25 and 50 mg/kg) and reference compounds: JNJ7777120 (25 mg/kg), indomethacin (10 mg/kg). Macrophages were pre-treated with two concentrations of tested compounds 100 and 10 µM.
  
  
  METHODS
  We examined anti-inflammatory and analgesic effects of the new H4R antagonists in the in vivo models of inflammation induced by carrageenan or zymosan. We assessed the level of cAMP and release of cytokines, ROS and NO in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Moreover, we assessed the affinity of the investigated compounds for histamine H1receptor in functional studies.
  
  
  RESULTS
  Both investigated compounds reduced paw edema, mechanical and thermal hyperalgesia in the carrageenan-induced acute inflammation. Moreover, administration of the investigated compounds resulted in decreased granulocyte influx and attenuated nociceptive reaction in the zymosan-induced peritonitis model. In the same model of inflammation, the investigated compounds reduced vascular permeability; however, this effect was observed only after the highest applied dose. Furthermore, the test compounds had no impact on cell viability in the experiments on RAW 264.7 macrophages. In these cells, stimulated with LPS, the test compounds decreased reactive oxygen species (ROS) production. They increased the cellular concentration of cAMP and attenuated the production of inflammatory cytokines such as TNFα and IL-1β. All results were comparable to those obtained for the reference compound JNJ7777120 with the exception of the impact on NO production. Nevertheless, this effect was similar to that obtained for the other reference compound rolipram, which is a phosphodiesterase 4 (PDE 4) inhibitor. Further experiments revealed that both of the investigated compounds possessed relatively low affinity for histamine H1receptor and do not inhibit the activity of the PDE 4B1 enzyme. In addition, all the effects of the investigated compounds in in vivo experiments were observed at doses that did not cause neurologic deficits in rotarod test and did not reduce spontaneous locomotor activity.
  
  
  CONCLUSIONS
  Our results demonstrate the anti-inflammatory and analgesic activity of the new aryl-1,3,5-triazine derivatives, which are primarily H4R-dependent.
authors.affiliation: Departament of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland. szczepan.mogilski@uj.edu.pl.
authors.forename: Szczepan
authors.identifier: http://orcid.org/0000-0002-3072-8890
authors.initials: S
authors.lastname: Mogilski
authors.affiliation: Departament of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kubacka
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Łażewska
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Więcek
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Krakow, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Głuch-Lutwin
authors.affiliation: Department of Radioligands, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Tyszka-Czochara
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.|Department of Clinical Immunology and Transplantology, Polish-American Institute of Pediatrics, Medical College, Jagiellonian University, Krakow, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Bukowska-Strakova
authors.affiliation: Departament of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002351:Carrageenan; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D000067996:RAW 264.7 Cells; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015054:Zymosan
chemical_list: D000700:Analgesics; D000893:Anti-Inflammatory Agents; D006633:Histamine Antagonists; D053583:Interleukin-1beta; D008024:Ligands; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D011968:Receptors, Histamine; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D002351:Carrageenan; D015054:Zymosan; D000242:Cyclic AMP
keywords: Cytokine; Edema; H4 receptor; Histamine; Inflammation; Pain; Triazine