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

ABSTRACT: 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.

SUBMITTER: Di Martino RMC

PROVIDER: S-EPMC8009478 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRepairing radiation-induced bone injuries remains a significant challenge in the clinic, and few effective medicines are currently available. Psoralen is a principal bioactive component of Cullen corylifolium (L.) Medik and has been reported to have antitumor, anti-inflammatory, and pro-osteogenesis activities. However, less information is available regarding the role of psoralen in the treatment of radiation-induced bone injury. In this study, we explored the modulatory effects of psoralen on skeletal stem cells and their protective effects on radiation-induced bone injuries.MethodsThe protective effects of psoralen on radiation-induced osteoporosis and irradiated bone defects were evaluated by microCT and pathological analysis. In addition, the cell proliferation, osteogenesis, and self-renewal of SSCs were explored. Further, the underlying mechanisms of the protective of psoralen were investigated by using RNA sequencing and functional gain and loss experiments in vitro and in vivo. Statistical significance was analyzed using Student's t test. The one-way ANOVA was used in multiple group data analysis.ResultsHere, we demonstrated that psoralen, a natural herbal extract, mitigated radiation-induced bone injury (irradiation-induced osteoporosis and irradiated bone defects) in mice partially by rescuing the stemness of irradiated skeletal stem cells. Mechanistically, psoralen restored the stemness of skeletal stem cells by alleviating the radiation-induced suppression of AKT/GSK-3β and elevating NRF2 expression in skeletal stem cells. Furthermore, the expression of KEAP1 in skeletal stem cells did not significantly change in the presence of psoralen. Moreover, blockade of NRF2 in vivo partially abolished the promising effects of psoralen in a murine model of irradiation-induced osteoporosis and irradiated bone regeneration.ConclusionsIn summary, our findings identified psoralen as a potential medicine to mitigate bone radiation injury. In addition, skeletal stem cells and AKT-GSK-3β and NRF2 may thus represent therapeutic targets for treating radiation-induced bone injury.

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

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