Department of Basic Science, Faculty of Medicine, University of Crete, Crete, Greece.
Institute of Molecular Biology & Biotechnology - FoRTH, Heraklion, Crete, Greece.
Glia. 2017 Aug;65(8):1376-1394. doi: 10.1002/glia.23170. Epub 2017 Jun 1.
BNN27, a member of a chemical library of C17-spiroepoxy derivatives of the neurosteroid DHEA, has been shown to regulate neuronal survival through its selective interaction with NGF receptors (TrkA and p75 ), but its role on glial populations has not been studied. Here, we present evidence that BNN27 provides trophic action (rescue from apoptosis), in a TrkA-dependent manner, to mature oligodendrocytes when they are challenged with the cuprizone toxin in culture. BNN27 treatment also increases oligodendrocyte maturation and diminishes microglia activation in vitro. The effect of BNN27 in the cuprizone mouse model of demyelination in vivo has also been investigated. In this model, that does not directly involve the adaptive immune system, BNN27 can protect from demyelination without affecting the remyelinating process. BNN27 preserves mature oligodendrocyte during demyelination, while reducing microgliosis and astrogliosis. Our findings suggest that BNN27 may serve as a lead molecule to develop neurotrophin-like blood-brain barrier (BBB)-permeable protective agents of oligodendrocyte populations and myelin, with potential applications in the treatment of demyelinating disorders.
BNN27 是神经甾体 DHEA 的 C17-螺环氧衍生物化学文库的成员，已被证明通过与神经营养因子受体（TrkA 和 p75）的选择性相互作用来调节神经元存活，但尚未研究其对神经胶质细胞群体的作用。在这里，我们提供的证据表明，当成熟的少突胶质细胞在培养中受到杯状蛋白毒素的挑战时，BNN27 以 TrkA 依赖性的方式提供营养作用（细胞凋亡的挽救）。BNN27 处理还增加了体外少突胶质细胞的成熟并减少了小胶质细胞的激活。还研究了 BNN27 在体内脱髓鞘的杯状蛋白模型小鼠中的作用。在这种模型中，它不直接涉及适应性免疫系统，BNN27 可以在不影响髓鞘再生过程的情况下保护免受脱髓鞘的影响。BNN27 在脱髓鞘过程中保护成熟的少突胶质细胞，同时减少小胶质细胞和星形胶质细胞的增生。我们的发现表明，BNN27 可以作为开发神经营养因子样血脑屏障（BBB）可渗透的少突胶质细胞和髓鞘保护剂的先导分子，具有治疗脱髓鞘疾病的潜在应用。
