Background

Cisplatin (CIS) is widely used in the chemotreatment of pediatric tumors. However, the CIS use is limited because of its high incidence of toxicity, mainly nephrotoxicity. Although there are many studies about CIS-related nephrotoxicity in animal models, only a few studies focus on juvenile animals. Because redox disturbances have been associated with kidney damage induced by CIS, this study aimed to compare the effectiveness of Ebselen and diphenyl diselenide (PhSe)₂ against nephrotoxicity induced by CIS in juvenile rats.

Methods

Juvenile Wistar rats were randomly divided into six groups: rats from groups I to III received an intraperitoneal (i.p.) injection with saline solution. The other groups received CIS (i.p., 6 mg/kg) on the first day. One hour before CIS injection and on the next four days, animals of groups III and V were intragastrically treated with Ebselen (11 mg/kg) whereas those from groups IV and VI received (PhSe)₂ (12 mg/kg). After 24 h of the last treatment, blood and kidney were collected, and the parameters of renal function and oxidative stress were determined.

Results

Kidney damage induced by CIS was confirmed by the increase of creatinine, urea and uric acid levels in the blood of juvenile rats. The renal oxidative disturbance was characterized by an increase in the levels of thiobarbituric acid reactive substances (TBARS), protein carbonyl, and nitrogen oxides (Nox), as well as the decrease in non-protein thiol content (NPSH), glutathione-S-transferase (GST), catalase (CAT) and superoxide dismutase (SOD) activities. CIS inhibited the activities of δ-aminolevulinic acid dehydratase (δ-ALA-D) and Na⁺, K⁺-ATPase and down-regulated the Nrf2/Keap-1/HO-1 pathway in the kidney of juvenile rats.

Conclusion

Both Ebselen and (PhSe)₂ modulated back to the normal levels all parameters altered by the CIS administration in the kidney of juvenile rats. Thus, this study shows that (PhSe)₂ was as effective as Ebselen in protecting the kidney against oxidative damage caused by CIS in rats.

中文翻译：

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二苯二硒化物在顺铂诱导的肾毒性幼鼠模型中与依布硒仑一样有效

背景

顺铂（CIS）被广泛用于儿童肿瘤的化学治疗。但是，CIS的使用受到限制，因为它的毒性很高，主要是肾毒性。尽管在动物模型中有许多有关CIS相关肾毒性的研究，但只有少数研究集中在幼年动物上。由于氧化还原紊乱与CIS引起的肾脏损害有关，因此本研究旨在比较依布硒仑和二苯二硒化物（PhSe）₂对CIS引起的幼鼠肾毒性的有效性。

方法

幼龄Wistar大鼠随机分为六组：第I至III组的大鼠腹腔注射（ip）盐溶液。其他组在第一天接受了CIS（腹膜内注射，6 mg / kg）。在CIS注射前一小时和接下来的四天，对第三和第五组的动物进行Ebselen（11 mg / kg）的胃内治疗，而第四和第六组的动物接受（PhSe）₂（12 mg / kg）。最后一次治疗24小时后，收集血液和肾脏，并测定肾功能和氧化应激的参数。

结果

幼年大鼠血液中肌酐，尿素和尿酸水平的升高证实了独联体诱导的肾脏损害。肾氧化紊乱的特征是硫代巴比妥酸反应性物质（TBARS），蛋白质羰基和氮氧化物（Nox）含量增加，以及非蛋白质硫醇含量（NPSH），谷胱甘肽-S-含量降低转移酶（GST），过氧化氢酶（CAT）和超氧化物歧化酶（SOD）活性。CIS抑制了幼鼠肾脏中δ-氨基乙酰丙酸脱水酶（δ-ALA-D）和Na ⁺，K ⁺ -ATPase的活性，并下调了Nrf2 / Keap-1 / HO-1通路。

结论

Ebselen和（PhSe）_2均调回正常水平，这是通过在幼年大鼠的肾脏中通过CIS给药改变的所有参数。因此，这项研究表明（PhSe）₂在保护肾脏免受CIS引起的氧化损伤方面与Ebselen一样有效。