Melatonin and Selenium Suppress Docetaxel-Induced TRPV1 Activation, Neuropathic Pain and Oxidative Neurotoxicity in Mice

Abstract

Docetaxel (DT) has been reported to positive therapeutic actions in the treatment of glioblastoma, breast tumors, and prostate cancers. However, it can also induce peripheral neuropathic pain and neurotoxicity as adverse effects. Expression level of TRPV1 cation channel is high in dorsal root ganglion (DRG), and its activation via capsaicin and reactive oxygen species (ROS) mediates peripheral neuropathic pain in mice. As cancer is known to increase the levels of ROS, the protective roles of melatonin (MT) and selenium (Se) were evaluated on the TRPV1-mediated neurotoxicity and pain in the DT-treated mice. Mice and TRPV1 expressing SH-SY5Y cells were equally divided into control, MT, Se, DT, DT+MT, and DT+Se groups. In the results of pain tests in the mice, we observed a decrease in DT-mediated mechanical and heat neuropathic pain by MT and Se. The results of plate reader assay and laser confocal microscopy image analyses indicated a protective role of MT and Se on the DT-induced increase of mitochondrial ROS, cytosolic ROS, apoptosis, lipid peroxidation, intracellular free Zn2+, Ca2+, and caspase-3 and -9 levels in the DRG and SH-SY5Y cells. MT and Se modulated DT-induced decreases of total antioxidant status, reduced glutathione and glutathione peroxidase in the DRG. However, the effects of DT were not observed in the non-TRPV1 expressing SH-SY5Y cells. Hence, MT and Se mediated protective effects against DT-induced adverse peripheral oxidative neurotoxicity and peripheral pain. These effects may be attributed to potent antioxidant properties of MT and Se.

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Funding

The study was supported by BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture and Industry Ltd, Göller Bölgesi Teknokenti, Isparta, Turkey (Project No: 2018-11). There is no financial disclosure of the current study.

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MN and KE formulated the present hypothesis, and MN was responsible for writing the report. KY was responsible for isolating the DRG and analyzing the intracellular Ca2+ concentration. MN was responsible for the laser confocal microscope analyses. KE was also responsible from plate reader analyses. ZSA made critical revision for the manuscript.

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Correspondence to Mustafa Nazıroğlu.

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Professor M. Nazıroğlu was employed by the company (BSN Health, Analyses, Innovation, Consultancy, Organization, Agriculture and Industry Ltd, Göller Bölgesi Teknokenti, Isparta, Turkey). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics Statement

This article does not contain any studies with human participants performed by any of the authors. This study was approved by the Local Ethical Committee of Burdur Mehmet Akif University (BMAU), Burdur, Turkey (Permit Numbers: 2019-60). The mice were cared in accordance with the guidelines of the Animal Care Committee of BMAU.

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Ertilav, K., Nazıroğlu, M., Ataizi, Z.S. et al. Melatonin and Selenium Suppress Docetaxel-Induced TRPV1 Activation, Neuropathic Pain and Oxidative Neurotoxicity in Mice. Biol Trace Elem Res (2020). https://doi.org/10.1007/s12011-020-02250-4

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Keywords

  • Apoptosis
  • Docetaxel
  • Glutathione
  • Hyperalgesia
  • Oxidative stress
  • TRPV1 channel