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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

  • Zeki Serdar Ataizi
  • Kemal Ertilav
  • Mustafa NazıroğluEmail author
Original Article
  • 6 Downloads

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.

Keywords

Apoptosis Docetaxel Hippocampus Inflammation Melatonin Mitochondrial oxidative cytotoxicity 

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

Notes

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/).

Authors’ 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.

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.

Compliance with ethical standards

Disclosures

None of the authors have any to disclose. All authors approved the final manuscript.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Departmant of NeurosurgeryYunus Emre General State HospitalEskişehirTurkey
  2. 2.Departmant of Neurosurgery, Faculty of MedicineSuleyman Demirel UniversityIspartaTurkey
  3. 3.Neuroscience Research CenterSuleyman Demirel UniversityIspartaTurkey
  4. 4.Drug Discovery Unit, BSN Health, Analysis and Innovation Ltd. Inc. TeknokentIspartaTurkey
  5. 5.Süleyman Demirel ÜniversitesiIspartaTurkey

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