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Novel Curcumin-Diethyl Fumarate Hybrid as a Dualistic GSK-3β Inhibitor/Nrf2 Inducer for the Treatment of Parkinson’s Disease
journal contribution
posted on 2020-08-03, 18:11 authored by 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 BellutiCommon
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.