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Novel Curcumin-Diethyl Fumarate Hybrid as a Dualistic GSK-3β Inhibitor/Nrf2 Inducer for the Treatment of Parkinson's Disease.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-07-14 , DOI: 10.1021/acschemneuro.0c00363 Rita Maria Concetta Di Martino 1 , Letizia Pruccoli 2 , Alessandra Bisi 1 , Silvia Gobbi 1 , Angela Rampa 1 , Ana Martinez 3 , Concepción Pérez 3 , Loreto Martinez-Gonzalez 3 , Maria Paglione 4 , Elia Di Schiavi 4 , Francesca Seghetti 1 , Andrea Tarozzi 2 , Federica Belluti 1
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-07-14 , DOI: 10.1021/acschemneuro.0c00363 Rita Maria Concetta Di Martino 1 , Letizia Pruccoli 2 , Alessandra Bisi 1 , Silvia Gobbi 1 , Angela Rampa 1 , Ana Martinez 3 , Concepción Pérez 3 , Loreto Martinez-Gonzalez 3 , Maria Paglione 4 , Elia Di Schiavi 4 , Francesca Seghetti 1 , Andrea Tarozzi 2 , Federica Belluti 1
Affiliation
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Common copathogenic factors, including oxidative stress and neuroinflammation, are found to play a vital role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Nowadays, owing to the multifactorial character of the diseases, no effective therapies are available, thus underlying the need for new strategies. Overexpression of the enzyme GSK-3β and downregulation of the Nrf2/ARE pathway are responsible for a decrease in antioxidant defense effects. These pieces of evidence underline the usefulness of dual GSK-3β inhibitors/Nrf2 inducers. In this regard, to design a dual modulator, the structures of a curcumin-based analogue, as GSK-3β inhibitor, and a diethyl fumarate fragment, as Nrf2 inducer, were combined. Among the hybrids, 5 and 6 proved to effectively inhibit GSK-3β, while 4 and 5 showed a marked ability to activate Nrf2 together to increase the neuronal resistance to oxidative stress. These last pieces of evidence translated into specific neuroprotective effects of 4 and 5 against PD pathological events including neurotoxicity elicited by α-synuclein aggregates and 6-hydroxydopamine. Hybrid 5 also showed neuroprotective effects in a C. elegans model of PD where the activation of GSK-3β is intimately involved in Nrf2 regulation. In summary, 5 emerged as an interesting multitarget derivative, valuable to be exploited in a multitarget PD perspective.
中文翻译：
新型姜黄素-富马酸二乙酯杂合物，作为治疗帕金森氏病的双重GSK-3β抑制剂/ Nrf2诱导剂。
已发现常见的共病原性因素，包括氧化应激和神经炎症，在神经退行性疾病（包括阿尔茨海默氏病（AD）和帕金森氏病（PD））的发展中起着至关重要的作用。如今，由于疾病的多因素特性，没有有效的治疗方法，因此需要新的策略。酶GSK-3β的过表达和Nrf2 / ARE途径的下调是抗氧化防御作用降低的原因。这些证据强调了双重GSK-3β抑制剂/ Nrf2诱导剂的有效性。在这方面，为了设计双重调节剂，将基于姜黄素的类似物（作为GSK-3β抑制剂）和富马酸二乙酯片段（作为Nrf2诱导剂）的结构进行了组合。在混合动力车中，5和6证明有效抑制GSK-3β，而4和5显示出显着的能力共同激活Nrf2以增加神经元对氧化应激的抵抗力。这些最后的证据转化为4和5对PD病理事件的特定神经保护作用，包括α-突触核蛋白聚集物和6-羟基多巴胺引起的神经毒性。杂种5还在PD的秀丽隐杆线虫模型中显示出神经保护作用，其中GSK-3β的激活与Nrf2调节密切相关。总而言之，有5种化合物作为有趣的多目标衍生物出现了，很有价值，可以在多目标PD方面加以利用。
更新日期：2020-09-02
中文翻译：
新型姜黄素-富马酸二乙酯杂合物，作为治疗帕金森氏病的双重GSK-3β抑制剂/ Nrf2诱导剂。
已发现常见的共病原性因素，包括氧化应激和神经炎症，在神经退行性疾病（包括阿尔茨海默氏病（AD）和帕金森氏病（PD））的发展中起着至关重要的作用。如今，由于疾病的多因素特性，没有有效的治疗方法，因此需要新的策略。酶GSK-3β的过表达和Nrf2 / ARE途径的下调是抗氧化防御作用降低的原因。这些证据强调了双重GSK-3β抑制剂/ Nrf2诱导剂的有效性。在这方面，为了设计双重调节剂，将基于姜黄素的类似物（作为GSK-3β抑制剂）和富马酸二乙酯片段（作为Nrf2诱导剂）的结构进行了组合。在混合动力车中，5和6证明有效抑制GSK-3β，而4和5显示出显着的能力共同激活Nrf2以增加神经元对氧化应激的抵抗力。这些最后的证据转化为4和5对PD病理事件的特定神经保护作用，包括α-突触核蛋白聚集物和6-羟基多巴胺引起的神经毒性。杂种5还在PD的秀丽隐杆线虫模型中显示出神经保护作用，其中GSK-3β的激活与Nrf2调节密切相关。总而言之，有5种化合物作为有趣的多目标衍生物出现了，很有价值，可以在多目标PD方面加以利用。
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