Effects of histamine H₄ receptor antagonist on the chemotherapy-induced anorexia in mice

抄録

INTRODUCTION

Cisplatin-based cancer chemotherapy often induces a biphasic pattern of anorexia, nausea and vomiting, which are classified as the acute phase (within 24 h following drug administration) and delayed phase (24 h after drug administration). To reduce these symptoms, serotonin 5-HT₃ receptor antagonists, neurokinin NK₁receptor antagonists, and corticosteroids are used. This regimen proved to be significantly effective to vomiting, but patients still experience anorexia and nausea, especially delayed phase of anorexia. Sickness behavior is known as adaptive behavioral changes that develop in ill during the course of systemic inflammation, and this symptom include malaise and loss of appetite. Since previous studies reported that antagonism of the histamine H₄ receptor has been shown to be anti-inflammatory, we investigated the involvement of H₄ receptor in the development of chemotherapy-induced anorexia in mice.

METHODS

Male DBA/2 mice were housed in individual food intake monitoring cages (FDM-300SW, Melquest, Toyama, Japan). On the day of the experiment, mice received cisplatin (7.5 mg/kg, i.p.) with or without subctaneous administration of 5-HT₃ receptor antagonist (granisetron 0.5 mg/kg), NK₁ receptor antagonists antagonist (fosaprepitant 30 mg/kg), corticosteroid (dexamethasone 0.5 mg/kg), and H₄ receptor antagonist (JNJ7777120 10 mg/kg), then their daily food intake was monitored for 3 days. Additionally, we examined the effect of H₄ receptor antagonist on the cisplatin-induced expression of Tumor Necrosis Factor (TNF)-α mRNA in the hypothalamus of mice.

RESULTS

Cisplatin induced anorexia within 24 hours after administration of the drug, and lasted during observation periods. Granisetron, fosaprepitant and dexamethasone slightly improved cisplatin-induced anorexia, but there were no significant differences. However, H₄ receptor antagonist significantly and completely abolished cisplatin-induced anorexia. Administration of cisplatin increased TNF-α mRNA expression in the hypothalamus and the time required to increase the expressions was comparable to the latency period of cisplatin-induced anorexia. In addition, pretreatment with H₄ receptor antagonist completely inhibited the expression.

CONCLUSION

These results suggest the TNF-α mRNA expression in the hypothalamus via H₄ receptor may contribute to the development of cisplatin-induced anorexia in mice and H₄ receptor antagonists have the potential to be medical candidates used as its treatment.