BNN-20, a synthetic microneurotrophin, strongly protects dopaininergic neurons in the "weaver" mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor
BNN-20, a synthetic microneurotrophin, strongly protects dopaininergic neurons in the "weaver" mouse, a genetic model of dopamine-denervation, acting through the TrkB neurotrophin receptor
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DOI：
10.1016/j.neuropharm.2017.04.043
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发表时间：
2017-07-15
影响因子：
4.7
通讯作者：
Angelatou, Fevronia
中科院分区：
文献类型：
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作者：
Botsakis, Konstantinos;Mourtzi, Theodora;Angelatou, Fevronia
神经营养因子是最有希望的治疗方法之一，旨在减缓或阻止甚至逆转帕金森病 (PD)。然而，在大多数情况下，它们不能轻易穿过人类血脑屏障 (BBB)。在此，我们建议使用小分子 17-β-spiro-[5-androsten-17,2'-oxiran]-3beta-ol (BNN-20) 作为 PD 的治疗药物，它是 DHEA 的合成类似物，可穿过 BBB，并且不会产生内分泌副作用。使用“weaver”小鼠（一种在黑质 (SN) 中表现出进行性多巴胺能神经变性的 PD 遗传模型），我们发现长期施用 (P1-P21) BNN-20 几乎完全保护多巴胺能神经元及其末梢，通过 i) 强大的抗凋亡作用，可能是通过原肌球蛋白受体激酶 B (Tr kappa B) 神经营养素受体介导的PI3K-Akt-NF-kappa B 信号通路，ii) 发挥有效的抗氧化作用，iii) 诱导显着的抗炎活性，以及 iv) 恢复脑源性神经营养因子 (BDNF) 水平。通过将“weaver”与NGL小鼠（双GFP/荧光素酶-NF-kappa B报告小鼠，NF-kappa B.GFP.Luc）杂交，我们获得了在所有体细胞中表达NF-kappa B报告基因的Weaver/NGL小鼠。生物发光成像检测到，对 Weaver/NGL 小鼠急性施用 BNN-20 会在大脑中诱导强烈的 NF-κ B 依赖性转录反应，但联合施用 TrkB 抑制剂 ANA-12 可以消除这种反应。这表明 BNN-20 通过 TrkB-PI3K-Akt-NF-kappa B 信号通路发挥其有益作用（至少部分）。
Neurotrophic factors are among the most promising treatments aiming at slowing or stopping and even reversing Parkinson's disease (PD). However, in most cases, they cannot readily cross the human blood brain-barrier (BBB).Herein, we propose as a therapeutic for PD the small molecule 17-beta-spiro-[5-androsten-17,2'-oxiran]-3beta-ol (BNN-20), a synthetic analogue of DHEA, which crosses the BBB and is deprived of endocrine side-effects. Using the "weaver" mouse, a genetic model of PD, which exhibits progressive dopaminergic neurodegeneration in the Substantia Nigra (SN), we have shown that long-term administration (P1-P21) of BNN-20 almost fully protected the dopaminergic neurons and their terminals, via i) a strong anti-apoptotic effect, probably mediated through the Tropomyosin receptor kinase B (Tr kappa B) neurotrophin receptor's PI3K-Akt-NF-kappa B signaling pathway, ii) by exerting an efficient antioxidant effect, iii) by inducing significant anti-inflammatory activity and iv) by restoring Brain-Derived Neurotrophic Factor (BDNF) levels. By intercrossing "weaver" with NGL mice (dual GFP/luciferase-NF-kappa B reporter mice, NF-kappa B.GFP.Luc), we obtained Weaver/NGL mice that express the NF-kappa B reporter in all somatic cells. Acute BNN-20 administration to Weaver/NGL mice induced a strong NF-kappa B-dependent transcriptional response in the brain as detected by bioluminescence imaging, which was abolished by co-administration of the TrkB inhibitor ANA-12. This indicates that BNN-20 exerts its beneficial action (at least in part) through the TrkB-PI3K-Akt-NF-kappa B signaling pathway.