Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
Endocrinology. 2010 Aug;151(8):3773-82. doi: 10.1210/en.2010-0061. Epub 2010 Jun 9.
Although chemotherapy with cisplatin is a widely used and effective cancer treatment, the undesirable gastrointestinal side effects associated with it, such as nausea, vomiting, and anorexia, markedly decrease patients' quality of life. To elucidate the mechanism underlying chemotherapy-induced anorexia, focusing on the hypothalamic ghrelin secretion-anorexia association, we measured hypothalamic ghrelin secretion in fasted and cisplatin-treated rats. Hypothalamic ghrelin secretion changes after vagotomy or administration of cisplatin. Cisplatin + rikkunshito, a serotonin 2C receptor antagonist or serotonin 3 receptor antagonist, was investigated. The effects of intracerebroventricular (icv) administration of ghrelin or the serotonin 2C receptor antagonist SB242084 on food intake were also evaluated in cisplatin-treated rats. Hypothalamic ghrelin secretion significantly increased in 24-h-fasted rats compared to freely fed rats and was markedly reduced 24 and 48 h after cisplatin treatment in cisplatin-treated rats compared to saline-treated rats, although their plasma ghrelin levels were comparable. In cisplatin-treated rats, icv ghrelin administration reversed the decrease in food intake, vagotomy partially restored hypothalamic ghrelin secretion, and hypothalamic serotonin 2C receptor mRNA expression increased significantly. Administration of rikkunshito (an endogenous ghrelin enhancer) or a serotonin 2C receptor antagonist reversed the decrease in hypothalamic ghrelin secretion and food intake 24 h after cisplatin treatment. Cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. Cerebral serotonin 2C receptor activation partially induces decrease in hypothalamic ghrelin secretion, and rikkunshito suppresses cisplatin-induced anorexia by enhancing this secretion.
虽然顺铂化疗是一种广泛应用且有效的癌症治疗方法，但与之相关的不良胃肠道副作用，如恶心、呕吐和厌食症，显著降低了患者的生活质量。为了阐明化疗引起的厌食症的机制，我们专注于下丘脑 ghrelin 分泌与厌食症的关联，测量了空腹和顺铂处理的大鼠的下丘脑 ghrelin 分泌。研究了迷走神经切断术或顺铂给药后下丘脑 ghrelin 分泌的变化。还研究了顺铂+利卡汀（一种 5-羟色胺 2C 受体拮抗剂或 5-羟色胺 3 受体拮抗剂）。还评估了脑室（icv）给予 ghrelin 或 5-羟色胺 2C 受体拮抗剂 SB242084 对顺铂处理大鼠摄食量的影响。与自由进食的大鼠相比，24 小时禁食的大鼠下丘脑 ghrelin 分泌显著增加，与生理盐水处理的大鼠相比，顺铂处理的大鼠在顺铂处理后 24 和 48 小时下丘脑 ghrelin 分泌明显减少，尽管它们的血浆 ghrelin 水平相当。在顺铂处理的大鼠中，脑室给予 ghrelin 逆转了摄食量的减少，迷走神经切断术部分恢复了下丘脑 ghrelin 分泌，下丘脑 5-羟色胺 2C 受体 mRNA 表达显著增加。给予利卡汀（一种内源性 ghrelin 增强剂）或 5-羟色胺 2C 受体拮抗剂可逆转顺铂处理后 24 小时下丘脑 ghrelin 分泌和摄食量的减少。顺铂诱导的厌食症是通过减少下丘脑 ghrelin 分泌介导的。脑 5-羟色胺 2C 受体激活部分导致下丘脑 ghrelin 分泌减少，利卡汀通过增强这种分泌来抑制顺铂引起的厌食症。
