Effects of a histamine H4 receptor antagonist on cisplatin-induced anorexia in mice
Effects of a histamine H4 receptor antagonist on cisplatin-induced anorexia in mice
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DOI：
10.1016/j.neulet.2018.04.019
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发表时间：
2018-05
影响因子：
2.5
通讯作者：
Kouichi Yamamoto;Rikuya Okui;A. Yamatodani
中科院分区：
文献类型：
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作者：
Kouichi Yamamoto;Rikuya Okui;A. Yamatodani
癌症化疗通常会引起胃肠道症状，如食欲减退、恶心和呕吐。止吐剂在抑制恶心和呕吐方面有效，但患者仍会出现厌食症。我们以前报道过化疗药物引起的厌食症与炎性细胞因子的增加有关。其他研究也报道了组胺H4受体的拮抗作用具有抗炎作用。在这项研究中，我们研究了H4受体在化疗诱导的小鼠厌食症发展中的作用。顺铂引起的厌食在给药后24 h内出现，持续3 d。每日注射5-HT3受体拮抗剂(格拉司琼)可抑制厌食症的早期阶段(第1天)，但不能抑制延迟阶段(第2天和第3天)。然而，皮质类固醇(地塞米松)或选择性H4受体拮抗剂(JNJ7777120)可消除厌食症的延迟阶段。顺铂显著增加下丘脑和脾组织肿瘤坏死因子-α基因的表达，且表达增加的时间与厌食症的起始期平行。此外，JNJ7777120可完全抑制该基因的表达。这些结果提示，肿瘤坏死因子-α基因通过H4受体的表达可能参与顺铂诱导的厌食症的发展，H4受体拮抗剂是潜在的有用的治疗方法。
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 H4receptor is anti-inflammatory. In this study, we investigated the involvement of the H4receptor 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-HT3receptor antagonist (granisetron). However, a corticosteroid (dexamethasone) or selective H4receptor antagonist (JNJ7777120) abolished the delayed phases of anorexia. Cisplatin significantly increased TNF-α 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-α mRNA expression via H4receptors may contribute to the development of cisplatin-induced anorexia, and that H4receptor antagonists are potentially useful treatments.