The Role of Ionic Homeostasis in Cisplatin-Induced Neurotoxicity: A Preliminary Study.

Cigdem Cengelli Unel,Kevser Erol

doi:10.5152/eurasianjmed.2018.17233

Cigdem Cengelli Unel, Kevser Erol

Open Access

https://doi.org/10.5152/eurasianjmed.2018.17233

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Abstract

The aim of the present study was to investigate the role of ionic homeostasis in cisplatin (cisdiamminedichloroplatinum (II), CDDP)-induced neurotoxicity. CDDP is a severely neurotoxic antineoplastic agent that causes neuronal excitotoxicity. According to some studies, calcium influx increases, whereas potassium efflux decreases neuronal death. Nimodipine and glibenclamide were used to analyze the role of ionic flows in CDDP-induced neurotoxicity in rat primary cerebellar granule cell (CGC) culture. CGC culture was prepared from the cerebella of Sprague Dawley 5-day-old pups. The submaximal concentration of CDDP was determined and then given with 1, 10, or 50 µM of drugs into culture. Neurotoxicity was investigated using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole) assay. One-way analysis of variance, Kruskal-Wallis H test, and Tukey test were applied for statistical analysis. CDDP induced neurotoxicity in a concentration-dependent manner. Neither nimodipine nor glibenclamide was able to protect CGCs against CDDP neurotoxicity. By blocking L-type voltage-gated calcium channels, nimodipine did not prevent CDDP neurotoxicity in CGCs. Ca2+ influx via these channels seemed to be insufficient to cause a change in CDDP-induced neurotoxicity. Similarly, glibenclamide failed to prevent CDDP neurotoxicity. Further studies are needed to elucidate the mechanisms of these preliminary results.

Highlights

Cisplatin (cis-diamminedichloroplatinum (II), CDDP) is a platinum-based antineoplastic agent widely used against a variety of cancers [1]
Ca2+ influx via these channels seemed to be insufficient to cause a change in CDDPinduced neurotoxicity
Primary cultures of cerebellar granule cell (CGC) were prepared from 5-day-old newborn Sprague–Dawley rats with modifications in the method described by Xu and Wojcik [15]

Summary

Introduction

Cisplatin (cis-diamminedichloroplatinum (II), CDDP) is a platinum-based antineoplastic agent widely used against a variety of cancers [1]. Its clinical benefits are limited owing to its adverse effects, such as ototoxicity, nephrotoxicity, cardiotoxicity, hepatotoxicity, and central and peripheral neurotoxicity [2]. Neurotoxicity is an important dose-limiting adverse effect that may cause dose reduction or drug cessation during therapy and reduction of the quality of life of patients. The neurotoxicity induced by CDDP is found to have active neuronal cell death features and has glutamate-dependent excitotoxic features [3]. CDDP affects calcium homeostasis and causes increased intracellular calcium concentrations [4]. The knowledge about the neurotoxicity of cerebellar granule cells (CGCs) induced by CDDP is limited

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