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Neural Glyoxalase Pathway Enhancement by Morin Derivatives in an Alzheimer's Disease Model.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-01-17 , DOI: 10.1021/acschemneuro.9b00566
Joel Frandsen 1 , Seoung-Ryoung Choi 1 , Prabagaran Narayanasamy 1
Affiliation  

The glyoxalase pathway (GP) is an antioxidant defense system that detoxifies metabolic byproduct methylglyoxal (MG). Through sequential reactions, reduced glutathione (GSH), glyoxalase I (glo-1), and glyoxalase II (glo-2) convert MG into d-lactate. Spontaneous reactions involving MG alter the structure and function of cellular macromolecules through the formation of inflammatory advanced glycation endproducts (AGEs). Accumulation of MG and AGEs in neural cells contributes to oxidative stress (OS), a state of elevated inflammation commonly found in neurodegenerative diseases including Alzheimer's disease (AD). Morin is a common plant-produced flavonoid polyphenol that exhibits the ability to enhance the GP-mediated detoxification of MG. We hypothesize that structural modifications to morin will improve its inherent GP enhancing ability. Here we synthesized a morin derivative, dibromo-morin (DBM), formulated a morin encapsulated nanoparticle (MNP), and examined their efficacy in enhancing neural GP activity. Cultured mouse primary cerebellar neurons and Caenorhabditis elegans were induced to a state of OS with MG and treated with morin, DBM, and MNP. Results indicated the morin derivatives were more effective compared to the parent compound in neural GP enhancement and preventing MG-mediated OS in an AD model.

中文翻译:

在阿尔茨海默氏病模型中,Morin衍生物增强了神经乙醛酸酶的途径。

乙二醛酶途径(GP)是一种抗氧化防御系统,可清除代谢副产物甲基乙二醛(MG)。通过顺序反应,还原型谷胱甘肽(GSH),乙二醛酶I(glo-1)和乙二醛酶II(glo-2)将MG转化为d-乳酸。涉及MG的自发反应通过形成炎症性晚期糖基化终产物(AGEs)来改变细胞大分子的结构和功能。神经细胞中MG和AGEs的积累有助于氧化应激(OS),这是一种在包括Alzheimer病(AD)在内的神经退行性疾病中常见的炎症加剧状态。Morin是一种常见的植物产生的类黄酮多酚,具有增强GP介导的MG排毒的能力。我们假设对morin的结构修饰将改善其固有的GP增强能力。在这里,我们合成了一种morin衍生物二溴莫林(DBM),配制了一种morin包裹的纳米颗粒(MNP),并检查了它们在增强神经GP活性方面的功效。MG诱导培养的小鼠原发性小脑神经元和秀丽隐杆线虫进入OS状态,并用morin,DBM和MNP处理。结果表明,在神经模型GP增强和AD模型中预防MG介导的OS方面,morin衍生物比母体化合物更有效。
更新日期:2020-01-21
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