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新型 1,2,4-噁二唑衍生物的体外合成及生物活性评价及在 3×Tg 小鼠中的体内评价。

Synthesis and Bioactivity Evaluation of a Novel 1,2,4-Oxadiazole Derivative in vitro and in 3×Tg Mice.

机构信息

Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC), Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100021, People's Republic of China.

Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation, Institute of Material Medical, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100050, People's Republic of China.

出版信息

Drug Des Devel Ther. 2022 Sep 25;16:3285-3296. doi: 10.2147/DDDT.S372750. eCollection 2022.

Abstract

AIM

Alzheimer's disease (AD) is the most common neurodegenerative disease whose patients suffered from cognitive impairments. In our study, a novel 1,2,4-Oxadiazole derivative wyc-7-20 was synthesized, which showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, β-amyloid (Aβ) clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected. The results demonstrated wyc-7-20 was potent in AD therapy.

PURPOSE

The pathological complexity of AD increased difficulties in medical research. To explore a new potential medical treatment for AD, a novel 1,2,4-Oxadiazole derivative (wyc-7-20) was designed, synthesized to explore the application in this study.

MATERIALS AND METHODS

Human neuroblastoma (SH-SY5Y) cells and human hepatocellular carcinoma (HepG2) cells were used to detect median lethal dose (LD50). HO and Aβ oligomers (AβOs) were respectively, added into SH-SY5Y cells to detect anti-ROS (reactive oxygen species) and anti-AβOs effects of wyc-7-20. 3×Tg mice were administered with wyc-7-20, and then Y maze test and Morris water maze (MWM) test were applied to detect cognitive improvements. Brain tissue samples were subsequently collected and analyzed using different techniques.

RESULTS

wyc-7-20 showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, Aβ clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected.

CONCLUSION

wyc-7-20 was potent in AD therapy.

摘要

目的

阿尔茨海默病(AD)是最常见的神经退行性疾病,其患者患有认知障碍。在我们的研究中,合成了一种新型 1,2,4-恶二唑衍生物 wyc-7-20,它在细胞水平上表现出低细胞毒性和强大的神经保护作用。在 wyc-7-20 治疗后,转基因动物模型中的认知障碍、β-淀粉样蛋白(Aβ)清除和 tau 病理表型得到改善。还检测到 AD 相关基因的表达逆转。结果表明 wyc-7-20 在 AD 治疗中有效。

目的

AD 的病理复杂性增加了医学研究的难度。为了探索 AD 的新的潜在治疗方法,设计并合成了一种新型 1,2,4-恶二唑衍生物(wyc-7-20),并在本研究中进行了应用探索。

材料和方法

人神经母细胞瘤(SH-SY5Y)细胞和人肝癌(HepG2)细胞用于检测半数致死剂量(LD50)。HO 和 Aβ 寡聚物(AβOs)分别加入 SH-SY5Y 细胞中,以检测 wyc-7-20 的抗 ROS(活性氧)和抗 AβOs 作用。3×Tg 小鼠给予 wyc-7-20,然后进行 Y 迷宫测试和 Morris 水迷宫(MWM)测试,以检测认知改善情况。随后收集脑组织样本并使用不同技术进行分析。

结果

wyc-7-20 在细胞水平上表现出低细胞毒性和强大的神经保护作用。在 wyc-7-20 治疗后,转基因动物模型中的认知障碍、Aβ 清除和 tau 病理表型得到改善。还检测到 AD 相关基因的表达逆转。

结论

wyc-7-20 在 AD 治疗中有效。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9733/9521684/1073940b21e2/DDDT-16-3285-g0001.jpg

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