Novel Curcumin-Diethyl Fumarate Hybrid as a Dualistic GSK-3β Inhibitor/Nrf2 Inducer for the Treatment of Parkinson’s Disease

Autor: Federica Belluti, Andrea Tarozzi, Alessandra Bisi, Angela Rampa, Maria Paglione, Francesca Seghetti, Elia Di Schiavi, Loreto Martínez-González, Silvia Gobbi, Concepción Pérez, Rita Maria Concetta Di Martino, Ana Martínez, Letizia Pruccoli
Přispěvatelé: Rita Maria Concetta Di Martino, Letizia Pruccoli, Alessandra Bisi, Silvia Gobbi, Angela Rampa, Ana Martinez, Concepción Pérez, Loreto Martinez-Gonzalez, Maria Paglione, Elia Di Schiavi, Francesca Seghetti, Andrea Tarozzi, Federica Belluti, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Consiglio Nazionale delle Ricerche, Di Martino, Rita Maria Concetta, Pruccoli, Letizia, Bisi, Alessandra, Gobbi, Silvia, Rampa, Angela, Martínez, Ana, Pérez, Concepción, Paglione, Maria, Di Schiavi, Elia, Seghetti, Francesca, Tarozzi, Andrea, Belluti, Federica, Di Martino, Rita Maria Concetta [0000-0003-2287-3331], Pruccoli, Letizia [0000-0002-0739-2102], Bisi, Alessandra [0000-0003-4662-4743], Gobbi, Silvia [0000-0001-9044-5377], Rampa, Angela [0000-0002-8028-8758], Martínez, Ana [0000-0002-2707-8110], Pérez, Concepción [0000-0001-7183-4035], Paglione, Maria [0000-0002-0921-940X], Di Schiavi, Elia [0000-0002-8179-6666], Seghetti, Francesca [0000-0003-0478-7341], Tarozzi, Andrea [0000-0001-7983-8575], Belluti, Federica [0000-0001-7983-8575]
Rok vydání: 2020
Předmět:
Zdroj: ACS Chemical Neuroscience
ACS chemical neuroscience 11 (2020): 2728–2740. doi:10.1021/acschemneuro.0c00363
info:cnr-pdr/source/autori:Di Martino, Rita Maria Concetta; Pruccoli, Letizia; Bisi, Alessandra; Gobbi, Silvia; Rampa, Angela; Martinez, Ana; Pérez, Concepción; Martinez-Gonzalez, Loreto; Paglione, Maria; Di Schiavi, Elia; Seghetti, Francesca; Tarozzi, Andrea; Belluti, Federica/titolo:Novel Curcumin-Diethyl Fumarate Hybrid as a Dualistic GSK-3? Inhibitor%2FNrf2 Inducer for the Treatment of Parkinson's Disease/doi:10.1021%2Facschemneuro.0c00363/rivista:ACS chemical neuroscience/anno:2020/pagina_da:2728/pagina_a:2740/intervallo_pagine:2728–2740/volume:11
Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1948-7193
DOI: 10.1021/acschemneuro.0c00363
Popis: 26 p.-8 fig.-2 tab.-1 graph. abst.-+9 p. mat. supl.-10 fig.-2 tab.
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.
This work was supported by the University of Bologna (RFO funds), MCIU (grant no. SAF2016-76693-R), and ISCiii CIBERNED (CB18/05/00040) and EDS, partially funded by the CNR project NUTR-AGE (FOE-2019, DSB.AD004.271).
Databáze: OpenAIRE
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