Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran.
Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Neurochem Res. 2019 Nov;44(11):2482-2498. doi: 10.1007/s11064-019-02865-7. Epub 2019 Sep 5.
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 day/gavage) for three consecutive weeks to induce OLGs degeneration with or without YM155 (1 mg kg day) 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.
杯状病毒（cup）模型靶向少突胶质细胞（OLGs）变性，常用于阐明脱髓鞘和髓鞘再生的机制。然而，这种经典模型耗时且脑损伤程度和行为缺陷在不同小鼠品系之间存在可变性（无论是时间上还是空间上）。我们旨在提供一种替代方案，该方案耗时更短且更具可重复性。通过连续 3 周给予杯（400mgkgday/gavage）来诱导 OLG 变性，并在有或没有 YM155（1mgkgday）的情况下，研究该分子对杯神经毒性的影响。杯和 YM155 的共同给药（cuYM）通过上调半胱天冬酶-9 和半胱天冬酶-3 加速成熟 OLG（MOG 阳性细胞）的内在凋亡。除了通过降低谷胱甘肽过氧化物酶和诱导丙二醛来刺激氧化应激外，cuYM 还加重了旷场和转棒测试中的行为缺陷。在 cuYM 组中，BIRC5、BIRC4 和 NAIP 的表达减少，但与杯组相比，其他凋亡抑制蛋白（cIAP1 和 cIAP2）的丰度没有明显变化。此外，计算机模拟分析验证了 YM155 直接中断了某些转录因子（如 Krüppel 样家族（Klf）、特异性蛋白（SPs）、髓样锌指（MZFs）、锌指蛋白（ZNFPs）和转录因子激活增强子结合蛋白（TFAPs））在靶基因启动子上的结合位点。总之，这种改良模型促进了 cup 诱导的氧化还原和凋亡信号，增加了行为缺陷，节省了时间，减少了变异性，并可用于早期评估新型神经保护剂在少突胶质病变中的作用。
