ERKs and mitochondria-related pathways are essential for glycyrrhizic acid-mediated neuroprotection against glutamate-induced toxicity in differentiated PC12 cells

Abstract

The present study focuses on the neuroprotective effect of glycyrrhizic acid (GA, a major compound separated from Glycyrrhiza Radix, which is a crude Chinese traditional drug) against glutamate-induced cytotoxicity in differentiated PC12 (DPC12) cells. The results showed that GA treatment improved cell viability and ameliorated abnormal glutamate-induced alterations in mitochondria in DPC12 cells. GA reversed glutamate-suppressed B-cell lymphoma 2 levels, inhibited glutamate-enhanced expressions of Bax and cleaved caspase 3, and reduced cytochrome C (Cyto C) release. Exposure to glutamate strongly inhibited phosphorylation of AKT (protein kinase B) and extracellular signal-regulated kinases (ERKs); however, GA pretreatment enhanced activation of ERKs but not AKT. The presence of PD98059 (a mitogen-activated protein/extracellular signal-regulated kinase kinase [MEK] inhibitor) but not LY294002 (a phosphoinositide 3-kinase [PI3K] inhibitor) diminished the potency of GA for improving viability of glutamate-exposed DPC12 cells. These results indicated that ERKs and mitochondria-related pathways are essential for the neuroprotective effect of GA against glutamate-induced toxicity in DPC12 cells. The present study provides experimental evidence supporting GA as a potential therapeutic agent for use in the treatment of neurodegenerative diseases.

Pharmacological Effects ofGlycyrrhizaspp. and Its Bioactive Constituents: Update and Review

“…Both compounds are known to attenuate glutamateinduced apoptotic alterations, including mitochondrial function and the expression of apoptosis-related proteins (Teng et al, 2014b;Wang et al, 2014). Moreover, although liquiritin could also activate Akt and glycogen synthase kinase 3β, both compounds apparently exhibit neuroprotective effects via activation of the extracellular signalregulated kinase pathway (Teng et al, 2014b).…”

Polysaccharide purified from Lycium barbarum protects differentiated PC12 cells against L-Glu-induced toxicity via the mitochondria-associated pathway

“…The inhibition of ERKs phosphorylation leads to suppressed Bcl-2 and Bcl-xL expressions (23), which may influence mitochondrial function. It has been previously demonstrated that L-Glu strongly suppressed the levels of ERKs phosphorylation in DPC12 cells (5). Furthermore, the activation of Akt is reported to inhibit the expression of pro-apoptotic proteins, including Bcl-2 family proteins (24), which may further regulate mitochondrial function.…”

“…Excessive accumulation of L-Glu leads to the collapse of mitochondrial membrane potential (MMP), which is initiated by B-cell lymphoma 2 (Bcl-2) family members including the pro-and anti-apoptotic proteins. As reported previously, L-Glu-induced cell apoptosis is associated with the activation of extracellular signal-regulated kinases (ERKs) and protein kinase B (Akt) (5). Akt is involved in regulating oxidative stress in neuronal cells, and ERKs participates in mitochondria-mediated apoptotic cell death (6).…”

“…5 ) were pretreated 10 and 30 µg/ml with LBPS02 for 3 h and then co-incubated with 20 mM L-Glu for another 24 h. Cells were incubated with 2 µM 5,5',6,6'-tetrachloro-1,1',3,3' etraethylbenzimidazolylcarbocyanine iodide (Sigma-Aldrich; Merck KGaA) at 37˚C for 10 min. The fluorescence intensity was detected via Nikon Eclipse TE 2000-S fluorescent microscope (x20; charge coupled device camera; Nikon Corporation, Tokyo, Japan).…”

SOD2 Mediates Amifostine‐Induced Protection against Glutamate in PC12 Cells

“…PC12 cell is a rat pheochromocytoma cell-line, used commonly in the study of neurons [ 21 ], especially dopaminergic neurons in vitro . And PC12 cells exposed to glutamate have been taken universally to investigate oxidative stress injury of neurological diseases [ 22 , 23 ].…”