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
| العنوان: | 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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| المؤلفون: | Nima Sanadgol, Mohammad Reza Sepand, Samaneh Ramezani-sefidar, Meysam Yazdankhah, Mohsen Shahlaei, Sajad Moradi, Samaneh Reiszadeh-Jahromi |
| المصدر: | Neurochemical Research. 44:2482-2498 |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Apoptosis, Inhibitor of apoptosis, medicine.disease_cause, Biochemistry, Neuroprotection, Corpus Callosum, Inhibitor of Apoptosis Proteins, Cuprizone, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Survivin, medicine, Animals, Promoter Regions, Genetic, Transcription factor, Base Sequence, Caspase 3, Chemistry, Intrinsic apoptosis, Imidazoles, Neurotoxicity, General Medicine, medicine.disease, Caspase 9, Cell biology, Mice, Inbred C57BL, Molecular Docking Simulation, Disease Models, Animal, Oligodendroglia, Oxidative Stress, 030104 developmental biology, NAIP, 030217 neurology & neurosurgery, Oxidative stress, Demyelinating Diseases, Naphthoquinones |
| الوصف: | 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 kruppel-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. |
| تدمد: | 1573-6903 0364-3190 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4f165341dd92e441cc858a365fae96fdTest https://doi.org/10.1007/s11064-019-02865-7Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....4f165341dd92e441cc858a365fae96fd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15736903 03643190 |
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