Alzheimer's disease (AD) is the most common type of senile dementia. A number of factors have been proposed regarding pathology of AD, such as presence of β-amyloid, and cholinergic and oxidative stress. SAK3 (ethyl 8'-methyl-2',5-dioxo-2-piperidin-1-ylspiro[cyclopentene-3,3'-imidazo[1,2-a]pyridine]-1-carboxylate) reduces β-amyloid deposition and improves cognitive functions in amyloid precursor protein knock-in mice. Scopolamine is used to induce in cell lines a cholinergic deficit that mimics AD. In order to evaluate the possible neuroprotective properties of SAK3, human neuroblastoma SH-SY5Y cells were pretreated with the compound (25-100 nM) and further incubated in the presence of scopolamine (2 mM). SAK3 inhibited scopolamine-induced cellular apoptosis (morphologically and by determination of pro- and anti-apoptotic factor levels), increase in ROS levels, decrease in choline acetyltransferase level, phosphorylation of NF-κB, activation of Akt, JNK and p38 intracellular signaling pathways, and elevation of proinflammatory cytokines IL-1β and IL-6, but not enhanced level of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). These results indicate SAK3 possessed protective properties against cholinergic deficit associated with anti-oxidant, anti-apoptotic and anti-inflammatory activities, suggesting that SAK3 might be a potential agent in the development of AD drug therapeutics.

中文翻译：

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SAK3 对东莨菪碱诱导的人神经母细胞瘤 SH-SY5Y 细胞胆碱能功能障碍的神经保护作用。


阿尔茨海默病（AD）是最常见的老年痴呆症类型。人们提出了许多与 AD 病理有关的因素，例如 β-淀粉样蛋白的存在以及胆碱能和氧化应激。 SAK3（8'-甲基-2',5-二氧代-2-哌啶-1-基螺[环戊烯-3,3'-咪唑并[1,2-a]吡啶]-1-甲酸乙酯）减少 β-淀粉样蛋白沉积并改善淀粉样前体蛋白敲入小鼠的认知功能。东莨菪碱用于在细胞系中诱导模拟 AD 的胆碱能缺陷。为了评估 SAK3 可能的神经保护特性，用该化合物 (25-100 nM) 预处理人神经母细胞瘤 SH-SY5Y 细胞，并在东莨菪碱 (2 mM) 存在下进一步孵育。 SAK3 抑制东莨菪碱诱导的细胞凋亡（形态学上以及通过测定促凋亡因子和抗凋亡因子水平）、ROS 水平增加、胆碱乙酰转移酶水平降低、NF-κB 磷酸化、Akt、JNK 和 p38 细胞内信号通路激活、促炎细胞因子 IL-1β 和 IL-6 升高，但 β 位点淀粉样前体蛋白裂解酶 1 (BACE1) 水平未升高。这些结果表明，SAK3 具有针对与抗氧化、抗凋亡和抗炎活性相关的胆碱能缺陷的保护特性，这表明 SAK3 可能是开发 AD 药物疗法的潜在药物。