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Sepantronium Bromide (YM155), A Small Molecule Survivin Inhibitor, Promotes Apoptosis by Induction of Oxidative Stress, Worsens the Behavioral Deficits and Develops an Early Model of Toxic Demyelination: In Vivo and In-Silico Study

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Abstract

Cuprizone (cup) model targets oligodendrocytes (OLGs) degeneration and is frequently used for the mechanistic understanding of de- and remyelination. Improperly, this classic model is time-consuming and the extent of brain lesions and behavioral deficits are changeable (both temporally and spatially) within a mouse strain. We aimed to offer an alternative, less time-consuming, and more reproducible cup model. Mice (C57BL/6) were treated with cup (400 mg kg−1 day−1/gavage) for three consecutive weeks to induce OLGs degeneration with or without YM155 (1 mg kg−1 day−1) to examine the effects of this molecule in cup neurotoxicity. Co-administration of cup and YM155 (cuYM) accelerated the intrinsic apoptosis of mature OLGs (MOG positive cells) through the upregulation of caspase-9 and caspase-3. In addition to the stimulation of oxidative stress via reduction of glutathione peroxidase and induction of malondialdehyde, behavioral deficits in both Open-field and Rota-rod tests were worsened by cuYM. In the cuYM group, the expression of BIRC5, BIRC4 and NAIP was reduced, but no significant changes were observed in the abundance of the other inhibitor of apoptosis proteins (cIAP1 and cIAP2) in comparison with the cup group. Moreover, in silico analysis validated that YM155 directly interrupts the binding sites of certain transcription factors, such as krüppel-like family (Klf), specificity proteins (SPs), myeloid zinc fingers (MZFs), zinc finger proteins (ZNFPs), and transcription factor activating enhancer-binding proteins (TFAPs), on the promoters of target genes. In conclusion, this modified model promotes cup-induced redox and apoptosis signaling, elevates behavioral deficits, saves time, minimizes variations, and can be employed for early evaluation of novel neuroprotective agents in oligodendropathies.

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Acknowledgements

The authors are grateful to all respected research staffs in the Pharmaceutical Science Research Center, Tehran University of Medical Sciences, Tehran, Iran, for their help with the study.

Funding

This study was funded by University of Zabol (UOZ-GR-9517–13).

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Authors and Affiliations

  1. Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran

    Samaneh Reiszadeh-Jahromi

  2. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad-Reza Sepand

  3. Department of Biology, Faculty of Basic Sciences, Razi University, Kermanshah, Iran

    Samaneh Ramezani-sefidar

  4. Nano Drug Delivery Research Center, School of Pharmacy, Kermanshah University of Medical Science, Kermanshah, Iran

    Mohsen Shahlaei & Sajad Moradi

  5. Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Meysam Yazdankhah

  6. Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran

    Nima Sanadgol

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  1. Samaneh Reiszadeh-Jahromi
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Reiszadeh-Jahromi, S., Sepand, MR., Ramezani-sefidar, S. et al. Sepantronium Bromide (YM155), A Small Molecule Survivin Inhibitor, Promotes Apoptosis by Induction of Oxidative Stress, Worsens the Behavioral Deficits and Develops an Early Model of Toxic Demyelination: In Vivo and In-Silico Study. Neurochem Res 44, 2482–2498 (2019). https://doi.org/10.1007/s11064-019-02865-7

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