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

Abstract

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.

Identification of bioactive compounds in Shaoyao‐Gancao decoction using β2‐adrenoceptor affinity chromatography

“…LQ is one of the primary active ingredients of Glycyrrhiza Radix and has various pharmacological activities, such as antidepression and neuroprotection [30,31]. In this study, we found that PF and LQ relaxed the K + -stimulated muscular constriction.…”

Daily administration of yokukansan and keishito prevents social isolation-induced behavioral abnormalities and down-regulation of phosphorylation of neuroplasticity-related signaling molecules in mice

“…This mechanism is very likely to be implicated in the effect of KST, since KST ameliorated ISO-induced behavioral deficits when the administration was started from week 0, but not from week 2 after starting ISO. Moreover, chemical constituents of YKS and KST have been reported to have neuroprotective effects [33–36], suggesting that these compounds protect central cholinergic systems from ISO-induced dysfunction. This hypothesis is currently under investigation in our laboratory.…”

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

“…Similarly, liquiritin, a main component of Glycyrrhiza Radix , also alleviates mitochondrial apoptotic alternations induced by glutamate predominantly through activation of ERK and Akt-GSK-3β signaling pathways [88]. Neurotoxin 6-hydroxydopamine (6-OHDA) induces initiation of mitochondria-regulated apoptotic cascade events in SH-SY5Y cells, which can be ameliorated by the administration of sulfuretin through inhibition of GSK-3β signaling and inactivation of NF-κB signaling [89].…”