Biochemical and histologic study of lethal cisplatin nephrotoxicity prevention by mirtazapine

doi:10.1016/S1734-1140(12)70855-1

Pharmacological Reports

Volume 64, Issue 3, May–June 2012, Pages 594-602

https://doi.org/10.1016/S1734-1140(12)70855-1 Get rights and content

Abstract

Background

Cisplatin is a platinum derivative frequently used in the chemotherapy of different solid tumors. This biochemical and histologic study investigated a possible protective effect of mirtazapine with regard to cisplatin-induced nephrotoxicity in the rat.

Methods

The animals were divided into 4 groups: 15 mg/kg mirtazapine + 10 mg/kg cisplatin, 30 mg/kg mirtazapine + 10 mg/kg cisplatin, only 10 mg/kg cisplatin and negative control (healthy) group. During 14 days, the treatment and treated control group took drugs, while the healthy animals were given distilled water on the same schedule. All animals were sacrificed by high-dose anesthesia at the end of the 14 days of treatment; their kidneys were removed and subjected to histologic and biochemical study.

Results

In both of the doses we used, mirtazapine decreased the levels of malondialdehyde, creatinine, blood urea nitrogen and myeloperoxidase activity when compared to cisplatin group. On the other hand, it increased total glutathione level in all doses. Slight histopathological findings were determined in mirtazapine groups when compared to cisplatin control group.

Conclusion

In the light of our results and literature knowledge, we can conclude that the protective effect of mirtazapine in cisplatin toxicity originates from its own antioxidant activity.

Introduction

Cisplatin is a non-cycle-dependent cytotoxic platinum derivative frequently used in different solid tumors, including gastric, testicular, ovarian, urologic, head and neck and other cancers [6, 17]. It causes serious toxicity to the hematopoietic, gastrointestinal, central and peripheral nervous and other organ systems [10]. One of its several dose-limiting toxicities, which can also force an interruption of treatment, is its renal toxicity [1]. Because of being tubular toxin, it can be used to induce nephrotoxicity in experimental studies [4]. After the cisplatin treatment, approximately 25–35% of the patients present evidence of acute tubular necrosis [12].

Oxidative damage is possibly an important mechanism in the pathogenesis of cisplatin nephrotoxicity. It was reported that cisplatin exerts nephrotoxicity through an increase in the production of excess free radicals and a reduction in the production of antioxidants [16, 30]. As a consequence, it has been hypothesized that antioxidant treatment could be useful in avoiding or reducing nephrotoxicity. Published studies have shown a protective effect of different antioxidants on nephrotoxicity caused by cisplatin [20, 29]. This nephrotoxicity remains one of the main doselimiting toxicities of cisplatin; studies directed at reducing this toxicity are continuing.

Mirtazapine, which was used in our study, is used for major depression. It has been shown that mirtazapine represses the production of enzymatic and non-enzymatic oxidation indicators while increasing the antioxidant parameters. Mirtazapine has also been reported to protect gastric tissue from the gastro-toxic effect of indomethacin [5]. This information suggests that mirtazapine could be a cytoprotective agent. No data on a possible protective effect of mirtazapine with regard to the renal toxicity of cisplatin could be found in a literature search. Our study aimed to examine, by biochemical and histological means, a possible protective effect of mirtazapine against the nephrotoxicity of cisplatin in the rat.

Section snippets

Animals

A total of 28 male Wistar albino rats with a weight varying from 210 to 230 g were procured by the Atatürk University Medical Research Center. The animals were fed at room temperature (22°C) prior to the experimentation.

Pharmacological study

The animals were divided into 4 groups: The two treatment groups, each consisting of 7 animals, was first given mirtazapine 15 and 30 mg/kg in distilled water by gastric gavage, while the 7 animals in the treated control group and the 7 untreated controls, or healthy animals,

Histopathological results of healthy group

Healthy rat kidney tissue was assessed as normal. As seen in Figure 1, no pathological finding was observed in glomerular, proximal and distal convoluted tubules and in interstitium. In kidney tubules, normal microvillus can be seen (PAS statin) with arrow.

Histopathological results of cisplatin control group

As seen in Figure 2a, serious cast formation was seen in the kidney tubules of cisplatin control group, on the other hand, significant swallow and severe desquamation was seen in epithelial cells. As seen in Figure 2b, significant tubular

Discussion

This biochemical and histologic study examined the effect of mirtazapine on cisplatin-induced nephrotoxicity. The nephrotoxicity of cisplatin, which is used to create an experimental model of nephrotoxicity, is well known [9, 31] A large number of experimental studies of the prevention of cisplatin nephrotoxicity have been published [28]. Cisplatin, in these publications, was given at a lower dose or for a shorter time than in our study; lower doses or shorter treatment with cisplatin resulted

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Biochemical and histologic study of lethal cisplatin nephrotoxicity prevention by mirtazapine

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Animals

Pharmacological study

Histopathological results of healthy group

Histopathological results of cisplatin control group

Discussion

J Lab Clin Med

Anal Biochem

J Invest Dermatol

Pharmacol Rep

J Lipid Res

Gastroenterology

J Pharmacol Sci

Eur J Cancer

Pharmacol Ther

Anal Biochem

Anal Biochem

Free Radic Biol Med

J Ren Nutr

Pharmacol Res

Pharmacol Res