Esculetin as a Bifunctional Antioxidant Prevents and Counteracts the Oxidative Stress and Neuronal Death Induced by Amyloid Protein in SH-SY5Y Cells

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 (A) 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 A1–42 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.

Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents

“…The exposure of Aβ 25–35 on the SH-SY5Y cells for 24 h exhibited significant ( p < 0.01) detrimental effects, when compared to the control, with a loss of cell viability of between 30% and 45% in five independent experiments conducted in triplicate. This reduction in cell viability in SH-SY5Y cells after Aβ 25–35 treatment was also reported in previous studies 64 , 65 . As the addition of Aβ 25–35 in SH-SY5Y cells precipitates apoptosis 66 , 67 , the neuroprotective activity of 6 and 7 on mitigating cellular apoptosis was examined at concentrations between 10 µM and 100 µM.…”

Esculetin Provides Neuroprotection against Mutant Huntingtin-Induced Toxicity in Huntington’s Disease Models

“…These findings therefore show the ability of ESC to protect the mitochondria from damage induced by mHTT. Several studies support these results showing the neuroprotective effects of ESC against neurodegeneration elicited by neurotoxins, such as oligomers of amyloid beta peptides and methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that target mitochondria [16,27]. Based on our results, we can hypothesize some mechanisms of mitochondrial protection mediated by ESC, including its ability to prevent the formation of mHTT aggregates toxicity toward mitochondria and thereby protect their activity.…”

Discovery and Evaluation of Enantiopure 9H-pyrimido[4,5-b]indoles as Nanomolar GSK-3β Inhibitors with Improved Metabolic Stability

“…Initially, we determined the concentrations of (R) -28 not associated to neurotoxicity by the MTT assay [ 14 ]. Therefore, concentrations of 1 and 5 µM were selected for the assays in SH-SY5Y cells, which were performed according to previously described protocols [ 15 , 16 , 17 ]. At the tested concentration of 1 μM, (R) -28 inhibited GSK3β activity in terms of inactive phospho-GSK3α/β (Ser21/9) increase and active phospho-GSK3α/β (Tyr279/Tyr216) decrease after 1 h of treatment in neuronal SH-SY5Y cells ( Figure S4 ).…”