Effects of a histamine H-4 receptor antagonist on cisplatin-induced anorexia in mice

摘要

Cancer chemotherapy often induces gastrointestinal symptoms such as anorexia, nausea, and vomiting. Antiemetic agents are effective in inhibiting nausea and vomiting, but patients still experience anorexia. We previously reported that chemotherapeutic agent-induced anorexia is associated with an increase of inflammatory cytokines. Other studies also reported that antagonism of the histamine H-4 receptor is anti-inflammatory. In this study, we investigated the involvement of the H-4 receptor in the development of chemotherapy-induced anorexia in mice. Cisplatin-induced anorexia occurred within 24 h of its administration and continued for 3 days. The early phase (day 1), but not the delayed phase (days 2 and 3), of anorexia was inhibited by the daily injection of a 5-HT3 receptor antagonist (granisetron). However, a corticosteroid (dexamethasone) or selective H-4 receptor antagonist (JNJ7777120) abolished the delayed phases of anorexia. Cisplatin significantly increased TNF-alpha mRNA expression in the hypothalamus and spleen, and the period of expression increase paralleled the onset period of anorexia. In addition, pretreatment with JNJ7777120 completely inhibited the increased expression. These results suggest that TNF-alpha mRNA expression via H-4 receptors may contribute to the development of cisplatin-induced anorexia, and that H-4 receptor antagonists are potentially useful treatments.