Department of Medical Biology, Faculty of Medicine, Bezmialem Vakif University, Adnan Menderes Bulvarı Vatan Caddesi, Fatih, TR-34093, Istanbul, Turkey.
Nutr Metab (Lond). 2013 Jan 12;10(1):7. doi: 10.1186/1743-7075-10-7.
Cisplatin, one of the most effective and potent anticancer drugs, is used in the treatment of a wide variety of both pediatric and adult malignancies. However, the chemotherapeutic use of cisplatin is limited by its serious side-effects such as nephrotoxicity and ototoxicity. Cisplatin chemotherapy induces a reduction in the antioxidant status, leading to a failure of the antioxidant defense against free-radical damage generated by antitumor drugs. Cisplatin-induced oxidative stress in the kidney was partially prevented by antioxidant treatments using superoxide dismutase, glutathione, selenium and flavonoids. Melatonin and its metabolites possess free-radical scavenging activity and it has been shown that they protect against cisplatin toxicity. However, the mechanism of the protective effects of melatonin against cisplatin-induced nephrotoxicity is still essentially unknown. We therefore designed this study to investigate the underlying mechanism of the protective effect of melatonin against cisplatin-induced renal damage in a rat nephrotoxicity model in vivo.
Twenty eight 8-week-old male Wistar rats were divided into four groups of control, melatonin treatment (4 mg/kg b.w i.p. for 10 days), cisplatin treatment (7 mg/kg b.w., i.p.) and melatonin and cisplatin combination treatment. Serum urea nitrogen (urea-N) and creatinine levels were measured. Histopathological changes were evaluated. In addition, we analyzed the expression levels of HO-1, Nrf2, NF-κB and AP-1 in Western blot analysis.
Both serum creatinine and urea nitrogen increased significantly following cisplatin administration alone; these values decreased significantly with melatonin co-treatment of cisplatin-treated rats. Histological analysis showed that cisplatin caused damage in the proximal tubular cells in the kidneys of cisplatin-treated rats; these changes were reversed by melatonin co-treatment. Upon Western blot analysis, melatonin treatment increased Nrf2 accumulation in the nuclear fraction, and increased the expression of HO-1 in the cytosolic fraction as compared to the cisplatin-treated rats. Expressions of NF-κB p65 and AP-1 were increased significantly in the kidneys of rats treated with cisplatin compared with the expression in the kidneys from the control, melatonin-only-treated and melatonin co-treated rats.
Our present data suggest that melatonin attenuates cisplatin-induced nephrotoxicity possibly by modulating Nrf2/HO-1 signaling.
顺铂是一种最有效和最有效的抗癌药物之一，用于治疗广泛的儿科和成人恶性肿瘤。然而，顺铂的化疗应用受到其严重副作用的限制，如肾毒性和耳毒性。顺铂化疗导致抗氧化状态降低，导致抗氧化防御系统无法对抗抗肿瘤药物产生的自由基损伤。超氧化物歧化酶、谷胱甘肽、硒和类黄酮等抗氧化剂治疗可部分预防顺铂引起的肾损伤中的氧化应激。褪黑素及其代谢产物具有自由基清除活性，已证明它们可防止顺铂毒性。然而，褪黑素对顺铂诱导的肾毒性的保护作用的机制在很大程度上仍然未知。因此，我们设计了这项研究，以在体内大鼠肾毒性模型中研究褪黑素对顺铂诱导的肾损伤的保护作用的潜在机制。
将 28 只 8 周龄雄性 Wistar 大鼠分为对照组、褪黑素治疗组（4mg/kg b.w. 腹腔注射 10 天）、顺铂治疗组（7mg/kg b.w.，腹腔注射）和褪黑素和顺铂联合治疗组。测量血清尿素氮（urea-N）和肌酐水平。评估组织病理学变化。此外，我们还通过 Western blot 分析分析了 HO-1、Nrf2、NF-κB 和 AP-1 的表达水平。
单独给予顺铂后，血清肌酐和尿素氮显着升高；这些值在用褪黑素联合治疗顺铂处理的大鼠中显着降低。组织学分析表明，顺铂导致顺铂处理大鼠肾脏近端肾小管细胞损伤；这些变化被褪黑素联合治疗逆转。通过 Western blot 分析，与顺铂处理的大鼠相比，褪黑素处理增加了核部分中 Nrf2 的积累，并增加了胞质部分中 HO-1 的表达。与对照组、仅用褪黑素处理组和褪黑素联合处理组相比，NF-κB p65 和 AP-1 的表达在顺铂处理的大鼠肾脏中显着增加。
我们目前的数据表明，褪黑素通过调节 Nrf2/HO-1 信号通路减轻顺铂诱导的肾毒性。
