Liquiritin modulates ERK- and AKT/GSK-3β-dependent pathways to protect against glutamate-induced cell damage in differentiated PC12 cells

Glutamate has a key role in the neuronal cell damage associated with Alzheimer’s and Parkinson’s diseases. Liquiritin (LQ), a major constituent of Glycyrrhiza Radix, possesses various pharmacological activities. The present study investigated the neuroprotective effect of LQ against glutamate-induced cell damage in the differentiated PC12 (DPC12) rat pheochromocytoma cell line. Pretreatment with 25 and 50 μM LQ for 3 h resulted in a significant increase in cell viability and inhibited excessive lactate dehydrogenase release in glutamate-exposed DPC12 cells. LQ also ameliorated glutamate-induced nuclear and mitochondrial apoptotic alterations, intracellular calcium overload and the abnormal expression of apoptosis-related proteins, including cytochrome c, B-cell lymphoma (Bcl)-2 and Bcl2-associated X protein. Treatment with LQ alone or in combination with glutamate was found to enhance the phosphoactivation of extracellular signal-regulated kinases (ERKs), AKT and its downstream element glycogen synthase kinase-3β (GSK3β), in a time-dependent manner. However, no effect was observed on the expression of total-ERKs, -AKT and -GSK3β. Furthermore, pre-incubation with 10 μM PD98059 or LY94002, inhibitors of ERK and phosphatidylinositide 3-kinase, respectively, for 30 min significantly suppressed the LQ-induced increase in glutamate-exposed DPC12 cell viability. To the best of our knowledge, the present study provides the first experimental evidence that LQ has a neuroprotective effect against glutamate toxicity in DPC12 cells, predominantly through the ERK and AKT/GSK-3β pathways. Therefore, LQ may have potential for the treatment of neurodegenerative diseases.