Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer’s disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood–brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD.

中文翻译：

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新型 TRKB 激动剂激活 TRKB 和下游 ERK 和 AKT 信号以保护 Aβ-GFP SH-SY5Y 细胞免受 Aβ 毒性

BDNF 减少和 TRKB 信号受损导致阿尔茨海默病 (AD) 中的神经变性。我们之前已经表明，香豆素衍生物 LM-031 增强了 CREB/BDNF/BCL2 通路。在这项研究中，我们探讨了 LM-031 类似物 LMDS-1 至 -4 是否可以作为 TRKB 激动剂来保护 SH-SY5Y 细胞免受 Aβ 毒性。通过使用 7,8-DHF 作为对照与 TRKB 结合的对接计算，所有四种 LMDS 化合物都显示出与 TRKB 的结构域 d5 结合的潜力。此外，所有四种 LMDS 化合物都对诱导 Aβ-GFP 表达的 SH-SY5Y 细胞表现出抗聚集和神经保护作用。TRKB 的敲低显着减弱了 TRKB 下游信号和这些 LMDS 化合物的神经突长出促进作用。其中，进一步检查了 LMDS-1 和 -2 的 TRKB 信号。ERK 抑制剂 U0126 或 PI3K 抑制剂渥曼青霉素的处理降低了 Aβ-GFP 细胞中的 p-CREB、BDNF 和 BCL2，表明神经保护作用是通过激活 TRKB 下游 ERK、PI3K-AKT 和 CREB ​​信号传导。LMDS-1 和 -2 是血脑屏障可渗透的，如平行人工膜渗透性测定所示。我们的结果证明了 LMDS-1 和 -2 如何可能作为 TRKB 激动剂在 Aβ 细胞中发挥神经保护作用，这可能揭示在 AD 治疗中的潜在应用。