Zirak Mohammad Reza, Rahimian Reza, Ghazi-Khansari Mahmoud, Abbasi Ata, Razmi Ali, Mehr Shahram Ejtemaei, Mousavizadeh Kazem, Dehpour Ahmad Reza
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, PO Box 13145-784, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Eur J Pharmacol. 2014 Sep 5;738:222-9. doi: 10.1016/j.ejphar.2014.05.050. Epub 2014 Jun 4.
Nephrotoxicity is one of the most important complications of cisplatin, a potent chemotherapeutic agent used in the treatment of various malignancies. 5-HT3 antagonists are widely used to counteract chemotherapy-induced emesis and new studies reveal that they poses notable anti-inflammatory properties. In current study, we investigated the effects of 5-HT3 antagonists on cisplatin induced nephrotoxicity in mice. To identify the underlying mechanism of renal protection by tropisetron, we investigated the probable involvement of alpha7 nicotinic acetylcholine receptor (α7nAChR). A single injection of cisplatin (20mg/kg; i.p) induced nephrotoxicity, 5-HT3 antagonists (tropisetron, granisetron and ondansetron,) were given twice daily for 3 day (3mg/kg; i.p). Finally animals were euthanized and blood sample was collected to measure urea and creatinin level. Also kidneys were removed for histopathological examination and biochemical measurements including glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, inducible nitric oxide synthase (iNOS) expression and inflammatory cytokines. Tropisetron decreased the expression of inflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and iNOS and improved histopathological damage and renal dysfunction. However other 5-HT3 antagonists, granisetron or ondansetron do not have any elicit effects on biochemical markers and histological damages. Since methyllycaconitine, antagonist of α7nAChR, was unable to reverse the beneficial effect of tropisetron, we concluded that this effect of tropisetron is not mediated by α7nAChR.Our results showed that tropisetron treatment markedly ameliorated the experimental cisplatin induced-nephrotoxicity and this effect might be 5-HT3 receptor and α7nAChR independent.
肾毒性是顺铂最重要的并发症之一，顺铂是一种用于治疗多种恶性肿瘤的强效化疗药物。5-羟色胺3（5-HT3）拮抗剂被广泛用于对抗化疗引起的呕吐，新研究表明它们具有显著的抗炎特性。在本研究中，我们调查了5-HT3拮抗剂对顺铂诱导的小鼠肾毒性的影响。为了确定托烷司琼肾脏保护作用的潜在机制，我们研究了α7烟碱型乙酰胆碱受体（α7nAChR）可能的参与情况。单次注射顺铂（20mg/kg；腹腔注射）可诱导肾毒性，5-HT3拮抗剂（托烷司琼、格拉司琼和昂丹司琼）每天腹腔注射两次，持续3天（3mg/kg）。最后对动物实施安乐死并采集血样以测量尿素和肌酐水平。同时摘除肾脏进行组织病理学检查和生化测量，包括谷胱甘肽（GSH）、丙二醛（MDA）、超氧化物歧化酶（SOD）活性、诱导型一氧化氮合酶（iNOS）表达和炎性细胞因子。托烷司琼降低了炎性分子包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和iNOS的表达，并改善了组织病理学损伤和肾功能障碍。然而，其他5-HT3拮抗剂，格拉司琼或昂丹司琼对生化指标和组织学损伤没有任何影响。由于α7nAChR拮抗剂甲基lycaconitine无法逆转托烷司琼的有益作用，我们得出结论，托烷司琼的这种作用不是由α7nAChR介导的。我们的结果表明，托烷司琼治疗显著改善了实验性顺铂诱导的肾毒性，并且这种作用可能独立于5-HT3受体和α7nAChR。
