Aryl-1,3,5-triazine ligands of histamine H4 receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide

Abstract

Objective and designHistamine H4 receptor (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.Materials and subjectsWe 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.TreatmentsIn 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.MethodsWe 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 H1 receptor in functional studies.ResultsBoth 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 H1 receptor 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.ConclusionsOur results demonstrate the anti-inflammatory and analgesic activity of the new aryl-1,3,5-triazine derivatives, which are primarily H4R–dependent.

Antinociceptive effects of novel histamine H3 and H4 receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse

“…TR‐7 showed low affinity for human H 3 receptors and therefore good (65 fold) selectivity towards H 4 receptors over H 3 receptors. The affinity of TR‐7 for the H 1 receptors has been measured in the guinea pig ileum (Mogilski et al ., ) and the pA 2 value they obtained (Table ) indicated a weak competitive interaction of this compound with the H 1 receptors present in this tissue.…”

“…Other anti‐inflammatory effects of TR‐7 were also found in a model of zymosan‐induced peritonitis, in which this compound decreased vascular permeability and the influx of inflammatory cells into the peritoneum. Further, TR‐7 reduced ROS, TNF‐α and IL‐1β production in RAW 264.7 macrophages (Mogilski et al ., ). The strong relationship of H 4 receptors with the immune system suggests that the antinociceptive action of TR‐7 may be due to a reduction in ongoing inflammatory processes at the site of injury during neuropathy and diminished activation of immune cells (especially mast cells), which release histamine in the periphery.…”

Roles of M1 and M2 Macrophages in Herpes Simplex Virus 1 Infectivity

“…Both zymosan and thioglycolate are used routinely to expand the PM population but are known to induce mild (zymosan) to strong (thioglycolate) inflammatory conditions (51,52). C57BL/6 mice were treated with zymosan or thioglycolate, and the PM were isolated as described in Materials and Methods, differentially polarized into M1 or M2 macrophages, and then infected with HSV-1 (10 PFU/cell) for 24 h. No significant differences in the levels of virus replication were found among the unpo-larized cells derived from zymosan-treated, thioglycolate-treated, or unpolarized PM (Fig.…”

Design and development of novel thiazolidin‐4‐one‐1,3,5‐triazine derivatives as neuro‐protective agent against cerebral ischemia–reperfusion injury in mice via attenuation of NF‐ĸB

“…Thiazolidin-4-one is a heterocyclic molecule wellknown for excellent pharmacological activities, for instance, anti-bacterial (Dwivedi, Devi, Asmat, Jain, & Sharma, 2016;Vicini, Geronikaki, Anastasia, Incerti, & Zani, 2006), anti-cancer (Joseph et al, 2013;Rashid et al, 2014), anti-viral (Murugesan et al, 2014), and anti-inflammatory (Vazzana, Terranova, Mattioli, & Sparatore, 2004). On the contrary, 1,3,5-triazine is also a versatile lead molecule exhibiting numerous biological activities, including anti-bacterial (Singh, Bhat, Kumawat, & Singh, 2014;Singh, Pathak, et al, 2012), antifungal (Singh, Bhat, Gahtori, & Singh, 2013;Singh, Pathak, et al, 2012;Vembu, Pazhamalai, & Gopalakrishnan, 2016), anti-cancer (Dao et al, 2015;Hodous et al, 2007;Popowycz et al, 2009) and more importantly anti-inflammatory action (Mogilski et al, 2017;Zacharie et al, 2018). Moreover, the pioneering study by Shrivastava et al reported a series of thiazolidin-4-one-1,3,5-triazine as potent NF-ĸB inhibitor for airway inflammation in cystic fibrosis (Srivastava et al, 2015).…”