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


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.


Apoptosis Docetaxel Hippocampus Inflammation Melatonin Mitochondrial oxidative cytotoxicity 



2-aminoethyl diphenylborinate




cumene hydroperoxide




2′,7′-dichlorodihydrofluorescin diacetate


Dulbecco’s Modified Eagle’s Medium




enzyme-linked immunosorbent assay


reduced glutathione


glutathione peroxidase


human embryonic kidney 293




interleukin 1beta


lipid peroxidation




mitochondrial membrane potential


poly (ADP-ribose) polymerase-1


polyunsaturated fatty acid


reactive oxygen species




total antioxidant status


tumor necrosis factor alpha


transient receptor potential


transient receptor potential 2



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 (

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.


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


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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