Abstract
Oxidative stress (OS) appears to be an important determinant during the different stages of progression of Alzheimer’s Disease (AD). In particular, impaired antioxidant defense mechanisms, such as the decrease of glutathione (GSH) and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2), a master regulator of antioxidant genes, including those for GSH, are associated with OS in the human AD brain. Among the neuropathological hallmarks of AD, the soluble oligomers of amyloid beta (Aβ) peptides seem to promote neuronal death through mitochondrial dysfunction and OS. In this regard, bifunctional antioxidants can exert a dual neuroprotective role by scavenging reactive oxygen species (ROS) directly and concomitant induction of antioxidant genes. In this study, among natural coumarins (esculetin, scopoletin, fraxetin and daphnetin), we demonstrated the ability of esculetin (ESC) to prevent and counteract ROS formation in neuronal SH-SY5Y cells, suggesting its profile as a bifunctional antioxidant. In particular, ESC increased the resistance of the SH-SY5Y cells against OS through the activation of Nrf2 and increase of GSH. In similar experimental conditions, ESC could also protect the SH-SY5Y cells from the OS and neuronal death evoked by oligomers of Aβ1–42 peptides. Further, the use of the inhibitors PD98059 and LY294002 also showed that Erk1/2 and Akt signaling pathways were involved in the neuroprotection mediated by ESC. These results encourage further research in AD models to explore the efficacy and safety profile of ESC as a novel neuroprotective agent.
Highlights
Several studies suggest that oxidative stress (OS) is an early event in the pathogenesis of Alzheimer’s disease (AD) [1,2]
Several studies report that the orto-dihydroxyl group and the α-pyrone ring present in coumarins ESC, FRAX and DAPH contribute to their radical scavenger and antioxidant activity [31,32]
Other studies suggest that the number of hydroxyl groups on the ring structure of coumarins is strictly correlated with their antioxidant effects [33]
Summary
Several studies suggest that oxidative stress (OS) is an early event in the pathogenesis of Alzheimer’s disease (AD) [1,2]. OS appears to be an important determinant during the different stages of progression of AD [3]. In this context, it is likely that a causal relationship occurs between. Among the different forms of Aß peptides, the soluble Aβ 1–42 peptides or shorter fragments seem to promote OS through their interaction with redox-active metals [5]. High OS in AD and its prodromal stage, mild cognitive impairment, have been presumed to be a consequence of compromised antioxidant defense mechanisms in both the blood and brain [6] OS by triggering N-methyl-d-aspartate receptor-dependent Ca2+ influxes leading to mitochondrial dysfunction with generation of reactive oxygen species (ROS) and subsequent neuronal death [4].
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