Kalafatakis Ilias, Patellis Alexandros, Charalampopoulos Ioannis, Gravanis Achille, Karagogeos Domna
Department of Basic Science, Faculty of Medicine, University of Crete, Crete, Greece.
Institute of Molecular Biology & Biotechnology - FoRTH, Heraklion, Crete, Greece.
J Neurosci Res. 2021 May;99(5):1474-1495. doi: 10.1002/jnr.24809. Epub 2021 Feb 13.
BNN20, a C17-spiroepoxy derivative of the neurosteroid dehydroepiandrosterone, has been shown to exhibit strong neuroprotective properties but its role in glial populations has not been assessed. Our aim was to investigate the effect of BNN20 on glial populations by using in vitro and in vivo approaches, taking advantage of the well-established lysophosphatidylcholine (LPC)-induced focal demyelination mouse model. Our in vivo studies, performed in male mice, showed that BNN20 treatment leads to an increased number of mature oligodendrocytes (OLs) in this model. It diminishes astrocytic accumulation during the demyelination phase leading to a faster remyelination process, while it does not affect oligodendrocyte precursor cell recruitment or microglia/macrophage accumulation. Additionally, our in vitro studies showed that BNN20 acts directly to OLs and enhances their maturation even after they were treated with LPC. This beneficial effect of BNN20 is mediated, primarily, through the neurotrophin receptor TrkA. In addition, BNN20 reduces microglial activation and their transition to their pro-inflammatory state upon lipopolysaccharides stimulation in vitro. Taken together our results suggest that BNN20 could serve as an important molecule to develop blood-brain barrier-permeable synthetic agonists of neurotrophin receptors that could reduce inflammation, protect and increase the number of functional OLs by promoting their differentiation/maturation.
BNN20是神经甾体脱氢表雄酮的C17 - 螺环氧衍生物，已被证明具有强大的神经保护特性，但其在神经胶质细胞群体中的作用尚未得到评估。我们的目的是利用成熟的溶血磷脂酰胆碱（LPC）诱导的局灶性脱髓鞘小鼠模型，通过体外和体内方法研究BNN20对神经胶质细胞群体的影响。我们在雄性小鼠身上进行的体内研究表明，在该模型中，BNN20治疗可导致成熟少突胶质细胞（OLs）数量增加。它减少了脱髓鞘阶段的星形胶质细胞积累，从而导致更快的髓鞘再生过程，而它不影响少突胶质前体细胞募集或小胶质细胞/巨噬细胞积累。此外，我们的体外研究表明，BNN20直接作用于OLs，即使在它们用LPC处理后也能促进其成熟。BNN20的这种有益作用主要是通过神经营养因子受体TrkA介导的。此外，BNN20在体外脂多糖刺激下可减少小胶质细胞活化及其向促炎状态的转变。综合我们的结果表明，BNN20可作为一种重要分子，用于开发可透过血脑屏障的神经营养因子受体合成激动剂，该激动剂可通过促进功能性OLs的分化/成熟来减轻炎症、保护并增加其数量。
