Activation of orexinergic and histaminergic pathway involved in therapeutic effect of histamine H4 receptor antagonist against cisplatin-induced anorexia in mice.

Abstract

We previously reported that hypothalamic tumor necrosis factor-alpha (TNF-α) mRNA expression via histamine H4 receptors contributes to the development of cisplatin-induced anorexia; however, its precise mechanisms remain unclear. It has been reported that chemotherapeutic agents induce the suppression of orexin neuron activity, and the administration of orexin inhibits chemotherapeutic agent-induced gastric discomfort. Other studies demonstrated that the central administration of TNF-α impairs the orexinergic system, and that orexin excites the histaminergic system. We investigated the involvement of orexinergic and histaminergic systems in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia. Cisplatin decreased the expression of prepro-orexin mRNA, which encodes precursors of orexin, in the hypothalamus of mice. The period of expression decreased in parallel with the onset of anorexia, and treatment with an H4 receptor antagonist (JNJ7777120, 10 mg/kg) inhibited the decrease in expression. The effect of the H4 receptor antagonist on cisplatin-induced anorexia in mice was antagonized by an orexin OX2 receptor antagonist (JNJ10397049, 5 mg/kg) rather than an orexin OX1 receptor antagonist (SB408124, 30 mg/kg). Although an OX2 receptor agonist (YNT-185, 20 mg/kg) or a histamine H3 receptor inverse agonist (ciproxifan, 1 mg/kg) inhibited the cisplatin-induced anorexia, the inhibitory effect of the OX2 receptor agonist was antagonized by an H3 receptor silent antagonist (VUF5681, 5 mg/kg). The combination of JNJ7777120 (10 mg/kg) and ciproxifan (0.5 mg/kg) completely resolved the cisplatin-induced anorexia. These results suggest that activation of the orexinergic and histaminergic pathway is involved in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia.

• Authors: Kouichi Yamamoto, Rikuya Okui, Atsushi Yamatodani
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 392 Issue 8 Pg. 925-936 (08 2019) ISSN: 1432-1912 [Electronic] Germany
• PMID: 30919010 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dioxanes
• Histamine Agonists
• Histamine Antagonists
• Imidazoles
• Indoles
• JNJ 10397049
• Orexin Receptors
• Orexins
• Phenylurea Compounds
• Piperazines
• Receptors, Histamine H4
• SB 408124
• 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
• ciproxifan
• Histamine
• Cisplatin

Topics

• Animals
• Anorexia (chemically induced, drug therapy, psychology)
• Antineoplastic Agents
• Cisplatin
• Dioxanes (therapeutic use)
• Eating (drug effects)
• Histamine (physiology)
• Histamine Agonists (therapeutic use)
• Histamine Antagonists (pharmacology)
• Imidazoles (therapeutic use)
• Indoles (therapeutic use)
• Male
• Mice
• Mice, Inbred DBA
• Orexin Receptors (drug effects)
• Orexins (biosynthesis, physiology)
• Phenylurea Compounds (therapeutic use)
• Piperazines (therapeutic use)
• Receptors, Histamine H4 (antagonists & inhibitors)
• Signal Transduction (drug effects)