Diammonium Glycyrrhizinate Upregulates PGC-1α and Protects against Aβ1-42-Induced Neurotoxicity

Mitochondrial dysfunction is a hallmark of beta-amyloid (A beta)-induced neurotoxicity in Alzheimer's disease (AD), and is considered an early event in AD pathology. Diammonium glycyrrhizinate (DG), the salt form of Glycyrrhizin, is known for its anti-inflammatory effects, resistance to biologic oxidation and membranous protection. In the present study, the neuroprotective effects of DG on A beta(1-42)-induced toxicity and its potential mechanisms in primary cortical neurons were investigated. Exposure of neurons to 2 mu M A beta(1-42) resulted in significant viability loss and cell apoptosis. Accumulation of reactive oxygen species (ROS), decreased mitochondrial membrane potential, and activation of caspase-9 and caspase-3 were also observed after A beta(1-42) exposure. All these effects induced by A beta(1-42) were markedly reversed by DG treatment. In addition, DG could alleviate lipid peroxidation and partially restore the mitochondrial function in A beta(1-42)-induced AD mice. DG also significantly increased the PGC-1 alpha expression in vivo and in vitro, while knocking down PGC-1 alpha partially blocked the protective effects, which indicated that PGC-1 alpha contributed to the neuroprotective effects of DG. Furthermore, DG significantly decreased the escape latency and search distance and increased the target crossing times of A beta(1-42)-induced AD mice in the Morris water maze test. Therefore, these results demonstrated that DG could attenuate A beta(1-42)-induced neuronal injury by preventing mitochondrial dysfunction and oxidative stress and improved cognitive impairment in A beta(1-42)-induced AD mice, indicating that DG exerted potential beneficial effects on AD.