Laboratory of Human and Animal Physiology, Department of Biology, University of Patras, Patras, 26500, Greece.
Department of Physiology, School of Medicine, University of Patras, Patras, 26500, Greece.
Neuropharmacology. 2020 Mar 15;165:107919. doi: 10.1016/j.neuropharm.2019.107919. Epub 2019 Dec 23.
BNN-20 is a synthetic microneurotrophin, long-term (P1-P21) administration of which exerts potent neuroprotective effect on the "weaver" mouse, a genetic model of progressive, nigrostriatal dopaminergic degeneration. The present study complements and expands our previous work, providing evidence that BNN-20 fully protects the dopaminergic neurons even when administration begins at a late stage of dopaminergic degeneration (>40%). Since neuroinflammation plays a critical role in Parkinson's disease, we investigated the possible anti-neuroinflammatory mechanisms underlying the pharmacological action of BNN-20. The latter was shown to be microglia-mediated, at least in part. Indeed, BNN-20 induced a partial, but significant, reversal of microglia hyperactivation, observed in the untreated "weaver" mouse. Furthermore, it induced a shift in microglia polarization towards the neuroprotective M2 phenotype, suggesting a possible beneficial shifting of microglia activity. This observation was further supported by morphometric measurements. Moreover, BDNF levels, which were severely reduced in the "weaver" mouse midbrain, were restored to normal even after short-term BNN-20 administration. Experiments in "weaver"/NGL (dual GFP/luciferase-NF-κВ reporter) mice using bioluminescence after a short BNN-20 treatment (P60-P74), have shown that the increase of BDNF production was specifically mediated through the TrkB-PI3K-Akt-NF-κB signaling pathway. Interestingly, long-term BNN-20 treatment (P14-P60) significantly increased dopamine levels in the "weaver" striatum, which seems to be associated with the improved motor activity observed in the treated mutant animals. In conclusion, our findings suggest that BNN-20 may serve as a lead molecule for new therapeutic compounds for Parkinson's disease, combining strong anti-neuroinflammatory and neuroprotective properties, leading to elevated dopamine levels and improved motor activity.
BNN-20 是一种合成的微神经生长因子，长期（P1-P21）给予其对“编织者”小鼠（一种进行性黑质纹状体多巴胺能变性的遗传模型）具有强大的神经保护作用。本研究补充并扩展了我们之前的工作，提供了证据表明，即使在多巴胺能神经元变性的晚期（>40%）开始给药，BNN-20 也能完全保护多巴胺能神经元。由于神经炎症在帕金森病中起着关键作用，我们研究了 BNN-20 药理学作用的可能的抗神经炎症机制。后者至少部分是由小胶质细胞介导的。事实上，BNN-20 诱导了未处理的“编织者”小鼠中小胶质细胞过度激活的部分但显著的逆转。此外，它诱导小胶质细胞向神经保护 M2 表型极化，这表明小胶质细胞活性可能发生有益的转变。形态计量学测量进一步支持了这一观察结果。此外，在“编织者”小鼠的中脑中严重降低的 BDNF 水平甚至在短期 BNN-20 给药后恢复正常。使用短期 BNN-20 处理（P60-P74）后，在“编织者”/NGL（双 GFP/荧光素酶-NF-κB 报告基因）小鼠中进行的实验表明，BDNF 产生的增加是通过 TrkB-PI3K-Akt-NF-κB 信号通路特异性介导的。有趣的是，长期 BNN-20 治疗（P14-P60）显著增加了“编织者”纹状体中的多巴胺水平，这似乎与治疗后突变动物观察到的运动活动改善有关。总之，我们的发现表明，BNN-20 可作为治疗帕金森病的新治疗化合物的先导分子，具有强大的抗炎和神经保护特性，导致多巴胺水平升高和运动活动改善。
