Diammonium Glycyrrhizinate Upregulates PGC-1α and Protects against Aβ(1–42)-Induced Neurotoxicity

Mitochondrial dysfunction is a hallmark of beta-amyloid (Aβ)-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 Aβ(1–42)-induced toxicity and its potential mechanisms in primary cortical neurons were investigated. Exposure of neurons to 2 µM Aβ(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 Aβ(1–42) exposure. All these effects induced by Aβ(1–42) were markedly reversed by DG treatment. In addition, DG could alleviate lipid peroxidation and partially restore the mitochondrial function in Aβ(1–42)-induced AD mice. DG also significantly increased the PGC-1α expression in vivo and in vitro, while knocking down PGC-1α partially blocked the protective effects, which indicated that PGC-1α contributed to the neuroprotective effects of DG. Furthermore, DG significantly decreased the escape latency and search distance and increased the target crossing times of Aβ(1–42)-induced AD mice in the Morris water maze test. Therefore, these results demonstrated that DG could attenuate Aβ(1–42)-induced neuronal injury by preventing mitochondrial dysfunction and oxidative stress and improved cognitive impairment in Aβ(1–42)-induced AD mice, indicating that DG exerted potential beneficial effects on AD.