Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative brain disorder, which is the most common form of dementia. Intensive efforts have been made to find effective and safe treatment against AD. Acetylcholinesterase inhibitors (AChEIs) have been widely used for the treatment of mild to moderate AD. In this study, we investigated the effect of Bis(9)-(−)-Meptazinol (B9M), a novel potential dual-binding acetylcholinesterase (AChE) inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. B9M (0.1 μg/kg, 0.3 μg/kg, and 1 μg/kg) was administered by subcutaneous injection into eight-month-old APP/PS1 transgenic mice for four weeks. Morris water maze, nest-building and novel object recognition were used to examine learning and memory ability. Aβ levels and Aβ plaque were evaluated by ELISA and immunochemistry. Our results showed that chronic treatment with B9M significantly improved the cognitive function of APP/PS1 transgenic mice in the Morris water maze test, nest-building test and novel object recognition test. Moreover, B9M improved cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of the AChE activity, Aβ plaque burden, levels of Aβ and the consequent activation of astrocytes and microglia in the brain of APP/PS1 transgenic mice. Most of important, the most effective dose of B9M in the present study is 1 μg/kg, which is one thousand of the dosage of Donepezil acted as the control treatment. Furthermore, B9M reduced Aβ plaque burden better than Donepezil. These results indicate that B9M appears to have potential as an effective AChE inhibitor for the treatment of AD with symptom-relieving and disease-modifying properties.

中文翻译：

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Bis(9)-(−)-Meptazinol 是一种新型双结合 AChE 抑制剂，可挽救 APP/PS1 转基因小鼠的认知缺陷和病理变化

阿尔茨海默氏病（AD）是一种进行性且不可逆的神经退行性脑部疾病，是痴呆症的最常见形式。为了寻找有效且安全的 AD 治疗方法，人们付出了巨大的努力。乙酰胆碱酯酶抑制剂（AChEI）已广泛用于治疗轻度至中度AD。在本研究中，我们研究了 Bis(9)-(−)-Meptazinol (B9M)（一种新型潜在的双结合乙酰胆碱酯酶 (AChE) 抑制剂）对学习和记忆能力的影响，以及 APP 中的潜在机制/PS1 AD 小鼠模型。通过皮下注射将 B9M（0.1 μg/kg、0.3 μg/kg 和 1 μg/kg）给予 8 个月大的 APP/PS1 转基因小鼠，持续 4 周。莫里斯水迷宫、筑巢和新奇物体识别用于检查学习和记忆能力。通过 ELISA 和免疫化学评估 Aβ 水平和 Aβ 斑块。我们的结果表明，B9M 的长期治疗显着改善了 APP/PS1 转基因小鼠在 Morris 水迷宫测试、筑巢测试和新物体识别测试中的认知功能。此外，B9M 通过抑制 AChE 活性、Aβ 斑块负荷、Aβ 水平以及随后激活 APP/PS1 转基因小鼠大脑中的星形胶质细胞和小胶质细胞相关的机制改善了 APP/PS1 小鼠的认知缺陷。最重要的是，本研究中B9M的最有效剂量为1μg/kg，是对照治疗剂量多奈哌齐剂量的一千倍。此外，B9M 比多奈哌齐更好地减少 Aβ 斑块负担。这些结果表明，B9M 似乎有潜力作为一种有效的 AChE 抑制剂，用于治疗 AD，具有缓解症状和缓解疾病的特性。