Involvement of MT2 receptors in protective effects of melatonin against cisplatin-induced gastrointestinal damage in mice

Abstract Melatonin (MLT) reportedly reduces side effects associated with certain antineoplastic agents. Accordingly, we investigated the effect of MLT on cisplatin (CP)-induced gastric emptying (GE) delay. Mice were intraperitoneally pretreated with vehicle (ethanol 5%; control group), MLT (5, 10, or 20 mg/kg), or N-acetylcysteine (NAC; 150 mg/kg), followed by CP treatment (5 mg/kg). Pharmacological modulation was analyzed using relevant receptor antagonists (luzindole: non-selective MT1/MT2 antagonist; 5 mg/kg or 4-P-PDOT: selective MT2 antagonist; 4 mg/kg) before treatment with MLT plus CP. All treatments were performed once daily for three days. GE was assessed using phenol red. Gut morphology was examined using scanning electron microscopy and optical microscopy. Compared with the control, CP decreased GE. Pretreatment with NAC and MLT (5 and 10 mg/kg) did not prevent CP-induced gastric dysmotility; however, pretreatment with 20 mg/kg MLT prevented this effect. In addition, luzindole and 4-P-PDOT suppressed MLT-mediated gastroprotection against cytotoxic effects of CP. CP caused degeneration of the gut mucosa, which was attenuated by MLT treatment. Thus, 20 mg/kg MLT prevented the GE delay and decreased CP-induced adverse effects on the gut mucosa. In addition, the gastroprotective activity was mediated via the MT2 receptor.

摘要 据报道，褪黑素（Melatonin，MLT）可减轻部分抗肿瘤药物引发的不良反应。据此，本研究探讨了褪黑素对顺铂（cisplatin，CP）诱导的胃排空（gastric emptying，GE）延迟的影响。实验小鼠先经腹腔给予溶媒（5%乙醇，对照组）、褪黑素（5、10或20 mg/kg）或N-乙酰半胱氨酸（N-acetylcysteine，NAC；150 mg/kg）预处理，随后予以顺铂（5 mg/kg）处理。在褪黑素联合顺铂给药前，使用相关受体拮抗剂（芦他吲哚（luzindole）：非选择性MT1/MT2受体拮抗剂；5 mg/kg，或4-P-PDOT：选择性MT2受体拮抗剂；4 mg/kg）开展药理学调控。所有处理均每日1次，连续3天。采用酚红法评估胃排空功能，通过扫描电子显微镜与光学显微镜观察肠道形态学变化。与对照组相比，顺铂可降低胃排空速率。N-乙酰半胱氨酸及5、10 mg/kg褪黑素预处理均未能阻断顺铂诱导的胃动力障碍；然而20 mg/kg褪黑素预处理可阻断该效应。此外，芦他吲哚与4-P-PDOT可抑制褪黑素介导的对抗顺铂细胞毒性的胃保护作用。顺铂可引发肠黏膜变性，褪黑素处理可缓解该病变。综上，20 mg/kg褪黑素可阻断顺铂诱导的胃排空延迟，并减轻其对肠黏膜的不良影响；该胃保护活性通过MT2受体介导。