5,6,7,4′-tetramethoxyflavanone attenuates nadph oxidase 1/4 and promotes sirtuin-1 to inhibit cell stress, senescence and apoptosis in aΒ25-35 –mediated sk-n-sh dysfunction

Abstract

Amyloidogenesis is a fundamental step of amyloid beta (Aβ) generation-induced toxicity that is commonly re-ported to disrupt neuronal circuits, function and survival in Alzheimer’s disease (AD). The neuroprotective effect of 5,6,7,4’-tetramethoxyflavanone (TMF) from Chormolaela odorata extract on brain degeneration and amyloi-dogenesis has previously been demonstrated. However, the mechanistic evidence for TMF’s effects is still unclear. In this study, we evaluated the neuroprotective effect of TMF in Aβ25-35-induced toxicity in SK-N-SH neuroblas-toma cells. Herein, we demonstrated that TMF exhibited potent antioxidant activity and significantly increased cell viability and decreased ROS production in a dose-dependent manner. Moreover, TMF reversed the effect of Aβ25-35, which caused energy deprivation and apoptosis, by decreasing the ratio of Bax/Bcl-xL and reducing mito-chondrial membrane potential (Δψm), caspase-3 expression, apoptotic cells, and attenuating glucose transporter (Glut-3) expression. In addition, TMF protected against Aβ25-35-induced cellular senescence by attenuating β-ga-lactosidase, p-21 and p-53 expression and promoted the expression of Sirt-1 and p-Rb. In addition, the effects of TMF on Aβ25-35 toxicity were related to the upregulation of phase II antioxidant and nuclear factor erythroid 2-related factor-2 (Nrf2) signaling, including superoxide dismutase (SOD), heme oxygenase (HO)-1, and nuclear translocation of Nrf2. Finally, we also found that TMF attenuated Aβ25-35-reduced synaptic plasticity by increasing the expression of synaptophysin and PSD-95, which was correlated with a decrease in acetylcholine esterase (AChE). Importantly, we found that the protective effects of TMF on Aβ25-35 were bidirectional, including marked inhibition of NADPH oxidase (NOX)-4 activity and partial activation of Sirt-1, which occurred prior to a reduction in the negative responses. Therefore, TMF may be useful for treating Aβ toxicity in AD.