Journal
ACS CHEMICAL NEUROSCIENCE
Volume 11, Issue 17, Pages 2728-2740Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.0c00363
Keywords
Curcumin analogues; Diethyl fumarate; Neurodegeneration; Nuclear factor-erythroid related factor 2; Glycogen synthase kinase-3 beta; Oxidative stress; Parkinson's disease
Funding
- University of Bologna (RFO funds), MCIU [SAF2016-76693-R]
- ISCiii CIBERNED [CB18/05/00040]
- EDS
- CNR project NUTR-AGE [DSB.AD004.271]
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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-3 beta 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-3 beta inhibitors/Nrf2 inducers. In this regard, to design a dual modulator, the structures of a curcumin-based analogue, as GSK-3 beta inhibitor, and a diethyl fumarate fragment, as Nrf2 inducer, were combined. Among the hybrids, 5 and 6 proved to effectively inhibit GSK-3 beta, 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 alpha-synuclein aggregates and 6-hydroxydopamine. Hybrid 5 also showed neuroprotective effects in a C. elegans model of PD where the activation of GSK-3 beta is intimately involved in Nrf2 regulation. In summary, 5 emerged as an interesting multitarget derivative, valuable to be exploited in a multitarget PD perspective.
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