Oxidative stress and neuroinflammation have been deeply associated with Alzheimer’s disease. DL0410 is a novel acetylcholinesterase inhibitor with potential anti-oxidative effects in AD-related animal models, while the specific mechanism has not been fully clarified. In this study, DL0410 was predicted to be related to the modification of cell apoptosis, oxidation-reduction process, inflammatory response and ERK1/ERK2 cascade by in silico target fishing and GO enrichment analysis. Then the possible protective effects of DL0410 were evaluated by hydrogen peroxide (H₂O₂)-induced oxidative stress model and lipopolysaccharides (LPS)-induced neuroinflammation model H₂O₂ decreased the viability of SH-SY5Y cells, induced malondialdehyde (MDA) accumulation, mitochondrial membrane potential (Δψm) loss and cell apoptosis, which could be reversed by DL0410 dose-dependently, indicating that DL0410 protected SH-SY5Y cells against H₂O₂-mediated oxidative stress. Western blot analysis showed that DL0410 increased the H₂O₂-triggered down-regulated TrkB, ERK and CREB phosphorylation and the expression of BDNF. In addition, TrkB inhibitor ANA-12, ERK inhibitor SCH772984 and CREB inhibitor 666-15 eliminated the inhibition of DL0410 on MDA accumulation and Δψm loss. Furthermore, DL0410 attenuates inflammatory responses and ROS production in LPS-treated BV2 cells, which is responsible for Nrf2 and HO-1 up-regulation. The present study demonstrates that DL0410 is a potential activator of the BDNF/TrkB/ERK/CREB and Nrf2/HO-1 pathway and may be a potential candidate for regulating oxidative stress and neuroinflammatory response in the brain. Together, the results showed that DL0410 is a promising drug candidate for treating AD and possibly other nervous system diseases associated with oxidative stress and neuroinflammation.

氧化应激和神经炎症已与阿尔茨海默氏病高度相关。DL0410是一种新型的乙酰胆碱酯酶抑制剂，在AD相关动物模型中具有潜在的抗氧化作用，但具体机理尚未完全阐明。在这项研究中，通过计算机靶标捕捞和GO富集分析，预计DL0410与细胞凋亡的修饰，氧化还原过程，炎症反应和ERK1 / ERK2级联有关。然后用过氧化氢（H ₂ O ₂）诱导的氧化应激模型和脂多糖（LPS）诱导的神经炎症模型H ₂ O ₂评估DL0410的可能的保护作用。降低SH-SY5Y细胞的活力，诱导丙二醛（MDA）积累，线粒体膜电位（Δψm）丧失和细胞凋亡，这可由DL0410剂量依赖性地逆转，表明DL0410保护SH-SY5Y细胞免受H ₂ O _2的侵害。介导的氧化应激。免疫印迹分析表明DL0410增加了H ₂ O ₂触发下调的TrkB，ERK和CREB磷酸化以及BDNF的表达。此外，TrkB抑制剂ANA-12，ERK抑制剂SCH772984和CREB抑制剂666-15消除了DL0410对MDA积累和Δψm损失的抑制作用。此外，DL0410减弱了LPS处理的BV2细胞的炎症反应和ROS产生，这是Nrf2和HO-1上调的原因。本研究表明，DL0410是BDNF / TrkB / ERK / CREB和Nrf2 / HO-1途径的潜在激活剂，并且可能是调节脑中氧化应激和神经炎症反应的潜在候选者。总之，结果表明DL0410是用于治疗AD和可能与氧化应激和神经炎症相关的其他神经系统疾病的有前途的候选药物。