Involvement of the ERK pathway in the protective effects of glycyrrhizic acid against the MPP+-induced apoptosis of dopaminergic neuronal cells

Abstract

Glycyrrhizic acid (GA), a major compound separated from Radix Glycyrrhizae, has been shwon to exert various biochemical effects, including neuroprotective effects. In the present study, we investigated the protective effects of GA against 1-methyl-4-phenylpyridinium (MPP+)-induced damage to differentiated PC12 (DPC12) cells. Compared with the MPP+-treated cells, GA markedly improved cell viability, restored mitochondrial dysfunction, suppressed the overexpression of cleaved poly(ADP-ribose) polymerase (PARP), and suppressed the overproduction of lactate dehydrogenase (LDH) and intracellular Ca2+ overload. The protective effects of GA on cell survival were further confirmed in primary cortical neurons. GA markedly increased the expression of phosphorylated extracellular signal-regulated kinase (p-ERK), as well as its migration from the cytoplasm to nucleus. PD98059, an inhibitor of ERK, blocked GA-enhanced ERK activation and reduced cell viability. However, pre-treatment with GA had no effects on the expression of phosphorylated AKT (p-AKT) and total AKT (t-AKT). These results indicate that the GA-mediated neuroprotective effects are associated with its modulation of multiple anti-apoptotic and pro-apoptotic factors, particularly the ERK signaling pathway. This study provides evidence supporting the use of GA as a potential therapeutic agent for the treatment of neurodegenerative diseases and neuronal injury.

The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma

“…Teng et al. showed that GL markedly upregulated the expression of phosphorylated extracellular signal‐regulated kinase (p‐ERK) and mediated its migration from cytoplasm to nucleus in dopaminergic neuronal cells. In contrast, Tu et al.…”

“…Some scientists also investigated the effect of GL on ERK signaling, but with different results. Teng et al [41] showed that GL markedly upregulated the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and mediated its migration from cytoplasm to nucleus in dopaminergic neuronal cells. In contrast, Tu et al [42] found that GL significantly repressed the concanavalin A-induced phosphorylation of ERK in vitro.…”

Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats

“…Interestingly however, while AKT inhibition decreased partially the hypoxic activity, ERK1/2 inhibition almost completely hinders it. Both AKT and ERK½ are two important signaling pathways involved in the integration of extracellular signals that are particularly important for cell survival and proliferation (Dey et al 2005 ;Teng et al 2014 ). Growth factors, cytokines and many other cellular stimuli trigger the AKT signaling pathway, activating in turn many different substrates involved in various cellular functions, such survival, growth, proliferation, metabolism and migration (reviewed in Engelman In the nervous system, the activation of AKT pathway is required in the synaptic plasticity processes such long-term potentiation and long-term depression (Kelly and Lynch 2000 ;Sanna et al 2002 ;Man et al 2003 ;Opazo et al 2003 ).…”

“…Besides, the pathways of protein kinase B (AKT) and extracellular signal-regulated kinases ½ (ERK1/2), are involved in major processes accomplishing a wide variety of neural tasks, including glucose metabolism (Engelman et al 2006 ), cellular apoptosis and survival (Teng et al 2014 ), differentiation (Chan et al 2013 ), neural proliferation and migration (Dey et al 2005 ), neuro-protection (Zhang et al 2014 ), neuro-degeneration (Fang et al 2014 ), and synaptic signaling (Yoshii and Constantine-Paton 2014 . Moreover, AKT and ERK1/2 in brain tissue participate in the modulation of dopaminergic (Beaulieu et al 2006 ), muscarinic (Rosenblum et al 2000 ), adrenergic (Taraviras et al 2002 ), serotonergic (Cowen 2007 ), GABAergic (Balasubramanian et al 2004 ) and adenosinergic (Wiese et al 2007 ) neurotransmission.…”

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

“…In another study, Ojha et al (2013) used biochemical and histopathological techniques to establish the cardioprotective effects of G. glabra (400 mg/kg) against oxidative stress in myocardial ischemia-reperfusion injury in rats (Ojha et al, 2013). ], improved function of mitochondria, and increased the expression and migration of p-ERK in DPC12 cells (Teng et al, 2014a) Glycyrurol, licopyranocoumarin MPP + -induced cell death Inhibited ROS production, limited activation of JNK, and caused decreasing in(ΔΨ mit ) in PC12D (Fujimaki et al, 2014) APP-PS1 Tg mice, B6C3-Tg (APPswe/PSEN1dE9) double-transgenic mice; JNK, c-Jun N-terminal kinase; CAT, catalase; DA, dopamine; DPC12, differentiated PC12 cells; GSH-Px, glutathione peroxidase; 4VO, four-vessel occlusion; MDA, malondialdehyde; MCAO, middle cerebral artery occlusion; NA, noradrenaline; MPP + , 1-methyl-4-phenylpyridinium; p-ERK, phosphorylated extracellular signal-regulated kinase; PTZ, pentylenetetrazole; 5-HT, serotonin; SNMC, Stronger Neo-Minophagen; STZ, streptozotocin; SOD, superoxide dismutase; TDC, 2′,4′-trihydroxychalcone.…”