Neuroprotective effects of coumarins in neurodegenerative disease models

Coumarins represent promising scaffolds for the design and development of novel polyfunctional drugs for the treatment and/or prevention of chronic neurodegenerative disorders including Alzheimer’s (AD), Parkinson’s and Huntington’s (HD) diseases. The aim of our research was to evaluate the potential antioxidant and neuroprotective effects of various natural coumarins such as esculetin (ESC), scopoletin, fraxetin and daphnetin in several experimental models of AD and HD. We used: i) human neuronal SH-SY5Y cells treated with tert-butyl hydroperoxide (t-BuOOH) and amyloid-β protein oligomers (OAβ), a specific neurotoxin for AD; ii) an inducible cell model (PC12 HD-Q74) and a transgenic Drosophila melanogaster model (HTT93Q, pan-neuronal expression), both of which express mutant huntingtin (HTT) exon 1 fragments, a typical feature of HD. The treatment with ESC prevented or counteracted the oxidative stress elicited by t-BuOOH in SH-SY5Y cells. ESC effectively increased intracellular glutathione levels and activated the translocation of Nrf2 into nucleus via Erk and Akt/GSK3β signalling pathways. ESC prevented both the oxidative damage and necrosis induced by OAβ. Further, ESC counteracted the early and late neurotoxic events, in terms of formazan exocytosis and necrosis, respectively, evoked by OAβ. The treatment with ESC partially modulated the aggregation of mutant HTT protein in PC12 HD-Q74 cells induced by doxycycline. ESC ameliorated the cell proliferation and counteracted the necrosis elicited by HTT74Q expression in PC12 HD-Q74 cells. ESC showed to counteract the oxidative stress as well as to increase the intracellular glutathione levels and restore the nuclear Nrf2 levels. In addition, ESC significantly decreased photoreceptor neurodegeneration in HTT93Q flies and enhanced in a dose-dependent manner the emergence of adult HD flies from the pupal case. ESC feeding also improved the shortening of median life span in HD flies. Our results encourage further research to better investigate the potential therapeutic profile of ESC as a neuroprotective agent.