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.

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.

Metformin-induced AMPK activation stimulates remyelination through induction of neurotrophic factors, downregulation of NogoA and recruitment of Olig2+ precursor cells in the cuprizone murine model of multiple sclerosis.

PURPOSE: Oligodendrocytes (OLGs) damage and myelin distraction is considered as a critical step in many neurological disorders especially multiple sclerosis (MS). Cuprizone (cup) animal model of MS targets OLGs degeneration and frequently used to the mechanistic understanding of de- and remyelination. The aim of this study was exploring the effects of metformin on the OLGs regeneration, myelin repair and profile of neurotrophic factors in the mice brain after cup-induced acute demyelination. METHODS: Mice (C57BL/6 J) were fed with chow containing 0.2% cup for 5 weeks to induce specific OLGs degeneration and acute demyelination. Next, the cup was withdrawn to allow one-week recovery (spontaneous remyelination). At the end of this period, mature OLGs markers, myelin-associated neurite outgrowth inhibitor protein A (NogoA), premature specific OLGs transcription factor (Olig2), anti-apoptosis marker (survivin), neurotrophic factors, and AMPK activation were monitored in the presence or absence of metformin (50 mg/kg body weight/day) in the corpus callosum (CC). RESULTS: Our finding indicated that consumption of metformin during the recovery period potentially induced an active form of AMPK (p-AMPK) and promoted repopulation of mature OLGs (MOG+ cells, MBP+ cells) in CC through up-regulation of BDNF, CNTF, and NGF as well as down-regulation of NogoA and recruitment of Olig2+ precursor cells. CONCLUSIONS: This study for the first time reveals that metformin-induced AMPK, a master regulator of energy homeostasis, activation following toxic demyelination could potentially accelerate regeneration and supports spontaneous demyelination. These findings suggest the development of new therapeutic strategies based on AMPK activation for MS in the near future. Graphical abstract An overview of the possible molecular mechanisms of action of metformin-mediated remyelinationa.