Quercetin attenuates cell apoptosis of oxidant-stressed SK-N-MC cells while suppressing up-regulation of the defensive element, HIF-1α

Abstract

Evidence is emerging that reactive oxygen species (ROS)-induced oxidative stress has a crucial role in the pathogenesis of neurodegenerative diseases. To find the effective therapies for neurodegenerative diseases, evaluation of the relevant molecular mechanisms is necessary. In the current study, we investigated the effects of hydrogen peroxide (H2O2)-induced oxidative stress on SK-N-MC cell death with focus on HIF-1α, Foxo3a and Notch1 signaling factors. Our results revealed that H2O2 reduced viability of cells through up-regulation of p53 followed by increase in Bax/Bcl2 ratio. In addition, H2O2 increased intracellular levels of HIF-1α, Foxo-3a and Notch intracellular domain (NICD). However, Quercetin decreased cell contents of HIF-1α, Foxo-3a and NICD as well as pro-apoptotic factors including p53 and Bax compared to H2O2-treated cells. Additionally, we found that HIF-1α down-regulation reduced Foxo3a and NICD contents parallel to up-regulation of p53 and Bax and led to further vulnerability to oxidative stress-induced cell death. In contrast, Notch inhibition resulted in HIF-1α/Foxo3a signaling pathway up-regulation, suggesting the bidirectional crosstalk between HIF-1α and Notch1. These results collectively suggest that ROS are involved in activation of both the defensive and pro-apoptotic pathways encompassing HIF-1α and p53, respectively. Regarding the HIF-1α-mediated neuroprotection role, elucidation of the molecular mechanism would certainly be essential for effective drug design against neurodegenerative diseases.

Keywords: HIF-1; neurodegenerative diseases; notch; oxidative stress; quercetin.