Background:Alzheimer’s disease (AD) is characterized by a progressive loss of episodic memory associated with amyloid-β peptide aggregation and the abnormal phosphorylation of the tau protein, leading to the loss of cholinergic function. Acetylcholinesterase (AChE) inhibitors are the main class ofdrugs used in AD therapy. Objective:The aim of the current study was to evaluate the potential of two tacrine-donepezil hybrid molecules (TA8Amino and TAHB3), which are AChE inhibitors, to induce neurodifferentiation and neuritogenesis in SH-SY5Y cells. Methods:The experiments were carried out to characterize neurodifferentiation, cellular changes related to responses to oxidative stress and pathways of cell survival in response to drug treatments. Results:The results indicated that the compounds did not present cytotoxic effects in SH-SY5Y or HepG2 cells. TA8Amino and TAHB3 induced neurodifferentiation and neuritogenesis in SH-SY5Y cells. These cells showed increased levels of intracellular and mitochondrial reactive oxygen species; the induction of oxidative stress was also demonstrated by an increase in SOD1 expression in TA8Amino and TAHB3-treated cells. Cells treated with the compounds showed an increase in PTEN(Ser380/Thr382/383) and AKT(Ser473) expression, suggesting the involvement of the AKT pathway. Conclusion:Our results demonstrated that TA8Amino and TAHB3 present advantages as potential drugs for AD therapy and that they are capable of inducing neurodifferentiation and neuritogenesis.

中文翻译：

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新型杂合乙酰胆碱酯酶抑制剂通过激活 AKT 通路诱导体外神经元细胞的分化和神经发生

背景：阿尔茨海默病 (AD) 的特征是与淀粉样蛋白 β 肽聚集和 tau 蛋白异常磷酸化相关的情景记忆的进行性丧失，导致胆碱能功能丧失。乙酰胆碱酯酶 (AChE) 抑制剂是用于 AD 治疗的主要药物类别。目的：本研究的目的是评估两种他克林-多奈哌齐杂合分子（TA8Amino 和 TAHB3），它们是 AChE 抑制剂，诱导 SH-SY5Y 细胞神经分化和神经发生的潜力。方法：进行实验以表征神经分化、与氧化应激反应相关的细胞变化以及响应药物治疗的细胞存活途径。结果：结果表明，化合物对SH-SY5Y或HepG2细胞均无细胞毒作用。TA8Amino 和 TAHB3 在 SH-SY5Y 细胞中诱导神经分化和神经发生。这些细胞显示出细胞内和线粒体活性氧水平增加；TA8Amino 和 TAHB3 处理的细胞中 SOD1 表达的增加也证明了氧化应激的诱导。用化合物处理的细胞显示 PTEN(Ser380/Thr382/383) 和 AKT(Ser473) 表达增加，表明 AKT 途径的参与。结论：我们的结果表明 TA8Amino 和 TAHB3 作为 AD 治疗的潜在药物具有优势，并且它们能够诱导神经分化和神经发生。TA8Amino 和 TAHB3 处理的细胞中 SOD1 表达的增加也证明了氧化应激的诱导。用化合物处理的细胞显示 PTEN(Ser380/Thr382/383) 和 AKT(Ser473) 表达增加，表明 AKT 途径的参与。结论：我们的结果表明 TA8Amino 和 TAHB3 作为 AD 治疗的潜在药物具有优势，并且它们能够诱导神经分化和神经发生。TA8Amino 和 TAHB3 处理的细胞中 SOD1 表达的增加也证明了氧化应激的诱导。用化合物处理的细胞显示 PTEN(Ser380/Thr382/383) 和 AKT(Ser473) 表达增加，表明 AKT 途径的参与。结论：我们的结果表明 TA8Amino 和 TAHB3 作为 AD 治疗的潜在药物具有优势，并且它们能够诱导神经分化和神经发生。