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Mitochondrial oxidative stress-induced brain and hippocampus apoptosis decrease through modulation of caspase activity, Ca2+ influx and inflammatory cytokine molecular pathways in the docetaxel-treated mice by melatonin and selenium treatments

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Abstract

Docetaxel (DOCE) is widely used to treat several types of glioblastoma. Adverse effects DOCE seriously limit its clinical use in several tissues. Its side effects on brain cortex and hippocampus have not been clarified yet. Limited data indicated a protective effect of melatonin (MLT) and selenium (SELEN) on DOCE-induced apoptosis, Ca2+ influx and mitochondrial reactive oxygen species (ROS) in several tissues except brain and hippocampus. The purpose of this study is to discover the protective effect of MLT and SELEN on DOCE-induced brain and hippocampus oxidative toxicity in mice. MLT and SELEN pretreatments significantly ameliorated acute DOCE-induced mitochondrial ROS production in the hippocampus and brain tissues by reducing levels of lipid peroxidation, intracellular ROS production and mitochondrial membrane depolarization, while increasing levels of total antioxidant status, glutathione, glutathione peroxidase, MLT, α-tocopherol, γ-tocopherol, vitamin A, vitamin C and β-carotene in the tissues. Furthermore, MLT and SELEN pretreatments increased cell viability and TRPM2 channel activation in the hippocampus and brain followed by decreased activations of TNF-α, IL-1β, IL-6, and caspase −3 and − 9, suggesting a suppression of calcium ion influx, apoptosis and inflammation responses. However, modulator role of SELEN on the values in the tissues is more significant than in the MLT treatment. MLT and SELEN prevent DOCE-induced hippocampus and brain injury by inhibiting mitochondrial ROS and cellular apoptosis through regulating caspase −3 and − 9 activation signaling pathways. MLT and SELEN may serve as potential therapeutic targets against DOCE-induced toxicity in the hippocampus and brain.

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Abbreviations

2-APB:

2-aminoethyl diphenylborinate

ADPR:

ADP-ribose

CPx:

cumene hydroperoxide

DCF:

2′,7′-dichlorofluorescein

DCFH-DA:

2′,7′-dichlorodihydrofluorescin diacetate

DMEM:

Dulbecco’s Modified Eagle’s Medium

DOCE:

docetaxel

ELISA:

enzyme-linked immunosorbent assay

GSH:

reduced glutathione

GSH-Px:

glutathione peroxidase

HEK293:

human embryonic kidney 293

IL:

interleukin

IL-1β:

interleukin 1beta

LPx:

lipid peroxidation

MLT:

melatonin

MMP:

mitochondrial membrane potential

PARP-1:

poly (ADP-ribose) polymerase-1

PUFA:

polyunsaturated fatty acid

ROS:

reactive oxygen species

SELEN:

selenium

TAS:

total antioxidant status

TNF-α:

tumor necrosis factor alpha

TRP:

transient receptor potential

TRPM2:

transient receptor potential 2

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Acknowledgements

The authors wish to thanks Dr. Bilal Çiğ for helping cytokine analyses, and technicians Musa Şimşek, Hulusi Gül and Fatih Şahin (BSN Health, Analysis and Innovation Ltd. Inc. Teknokent, Isparta, Turkey) for the helping the animal experiments, laser confocal microscope, HPLC and antioxidant analyses. Abstract of the current study will be presented in the 4th International Brain Research School, 24-30 June 2019, Isparta, Turkey (http://2019.brs.org.tr/).

Funding

The study was supported by BSN Health, Analysis and Innovation Ltd. Inc. Teknokent, Isparta, Turkey (Project No: 2018-10). There is no financial disclosure for the current study.

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Authors and Affiliations

  1. Departmant of Neurosurgery, Yunus Emre General State Hospital, Eskişehir, Turkey

    Zeki Serdar Ataizi

  2. Departmant of Neurosurgery, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey

    Kemal Ertilav

  3. Neuroscience Research Center, Suleyman Demirel University, Isparta, Turkey

    Mustafa Nazıroğlu

  4. Drug Discovery Unit, BSN Health, Analysis and Innovation Ltd. Inc. Teknokent, Isparta, Turkey

    Mustafa Nazıroğlu

  5. Süleyman Demirel Üniversitesi, Tıp Fakültesi, Biyofizik Anabilim Dalı, TR-32260, Isparta, Turkey

    Mustafa Nazıroğlu

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  1. Zeki Serdar Ataizi
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Contributions

ZSA and MN formulated the present hypothesis. MN was responsible for writing the report. MN and KE were responsible analyzing the spectrophotometer and plate reader. ZSA and KE made also critical revision for the manuscript.

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Correspondence to Mustafa Nazıroğlu.

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Ataizi, Z.S., Ertilav, K. & Nazıroğlu, M. Mitochondrial oxidative stress-induced brain and hippocampus apoptosis decrease through modulation of caspase activity, Ca2+ influx and inflammatory cytokine molecular pathways in the docetaxel-treated mice by melatonin and selenium treatments. Metab Brain Dis 34, 1077–1089 (2019). https://doi.org/10.1007/s11011-019-00428-x

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