Neuroprotective Effects of Rhynchophylline Against A beta(1-42)-Induced Oxidative Stress, Neurodegeneration, and Memory Impairment Via Nrf2-ARE Activation

摘要

Extensive studies have shown that oxidative stress is a crucial pathogenic factor in Alzheimer's disease (AD). Nuclear factor E2-related factor 2 (Nrf2) is a master cytoprotective regulator against oxidative stress, and thus represents an attractive therapeutic target in AD. The goal of our study is to investigate the contribution of Nrf2 in Rhynchophylline (Rhy)-induced neuroprotection in AD. The data showed that intraperitoneal administration of Rhy (10 or 20 mg/kg) could ameliorate A beta(1-42)-induced cognitive impairment, evidenced by performance improvement in memory tests. The result of Antioxidant response element (ARE)-luciferase activity assay indicated that Rhy treatment improved ARE promoter activity. The results of reactive oxygen species (ROS), malondialdehyde (MDA) and glutathione (GSH) assessment in the frontal cortex and hippocampus showed that Rhy treatment could attenuate A beta(1-42)-induced oxidative stress to some extent, evidenced by reversion of these cytokines compared to A beta(1-42) + Veh group. Rhy treatment also restored expression of Nrf2 and its downstream protein heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (NOQ1), and recombinant glutamate cysteine ligase, modifier subunit (GCLM) in the frontal cortex and hippocampus of A beta(1-42)-treated mice. In addition, to investigate whether activation of Nrf2-mediated pathway is responsible for the neuroprotection of Rhy, Nrf2 siRNA was used in human neuroblastoma cells (SH-SY5Y). Interestingly, the results showed that the protective effects of Rhy, including anti-oxidative, anti-apoptosis and elevation of Nrf2 and its downstream proteins, were abolished in Nrf2 siRNA-transfected cells. These findings indicate that Rhynchophylline is protective against A beta(1-42)-induced neurotoxicity via Nrf2-ARE activation, and suggest that Rhy may serve as a potential candidate and promising Nrf2 activator for management of AD.