Orientin Inhibits Oxidative Stress And Alleviates Cognitive Deficits In Aβ_1-42-induced Mouse Model Of Alzheimer’s Disease

Backgroud:Alzheimer’s disease (AD) is the most common form of neurodegeneration disease, and is characterized by progressive decline of memory and cognitive function and personality impairment. The pathological hallmarks of AD include the accumulation of extracellular beta-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) consisting of hyperphosphortheylated tau protein。 Aβ1-42-induced oxidative stress plays a critical role in the progression of AD. Anti-oxidative treatment might be a potential strategy for AD. Increasing evidence suggested that Orientin (Ori) could ameliorate mitochondrial function and inhibit oxidative stress and apoptsis.Objectives:The aims of this study are:1) to determine the effects of Ori on Aβ1-42-induced oxidative stress in AD model mice; 2) to explore the mechanism underlying Ori on Ap1-42-induced oxidative stress.Methods:AD models were made by injecting Aβ1-42 into the bilateral hippocampus fo mice. The mice were randomly assigned to three groups:the normal mice Aβ1-42 induced AD mice with saline, and Aβ1-42-induced AD mice with Ori (5 mg/kg), and were injected intraperitoneally once a day for 15 days. Learning and memory impairment was tested by Morris water maze. Mitochondrial function and reactive oxygen species (ROS) production were measured by JC-1 and DCFH-DA analysis. The levels of 8-hydroxy-2-de-axyguanine (8-OHdG),3-Neurotrophin (3-NT),4 Hydroxynonenal (4-HNE) were measured by the ELISA kits. The activity of Nrf2/HO-1 signaling pathway was determined by western blotting.Results:Ori could significantly attenuate the cognitive impairment in Aβ1-42-induced AD mice. After treated with Ori, the levels of ROS,8-OHdG,3-NT,4-HNE were markedly decreased. Ori ameliorated mitochondrial dysfunction and inhibited the cellular apoptosis in the hippocampus of Aβ1-42-induced AD mice. Ori activated the Nrf2/HO-1 signaling pathway by increasing the nuclear translocation of Nrf2 and upregulation of HO-1.Conclusion:Our results showed that Ori inhibited the cellular apoptosis induced by Aβ1-42 and ameliorated cognitive deficits in AD mice. In addition, Ori activated Nrf2/ ARE signaling pathways and alleviated mitochondrial dysfunction, which could lead to oxidative stress and downstream cascades. These data suggested that Ori might be a promising candidate drug for the treatment of AD.