Ginsenoside Rd promotes glutamate clearance by up-regulating glial glutamate transporter GLT-1 via PI3K/AKT and ERK1/2 pathways

Abstract

Ginsenoside Rd (Rd), one of the main active ingredients in Panax ginseng, has been showed to protect against ischemic cerebral damage both in vitro and in vivo. However, the underlying mechanism of Rd is largely unknown. Excessive extracellular glutamate causes excitatory toxicity, leading to cell death, and neurodegenerative processes after brain ischemia. The clearance of extracellular glutamate by astrocytic glutamate transporter GLT-1 is essential for neuronal survival after stroke. Here we investigated the effects of Rd on the levels of extracellular glutamate and the expression of GLT-1 in vivo and in vitro. After rat middle cerebral artery occlusion, Rd significantly increased the mRNA and protein expression levels of GLT-1, and reduced the burst of glutamate as revealed by microdialysis. Consistently, specific glutamate uptake by cultured astrocytes was elevated after Rd exposure. Furthermore, we showed that Rd increased the levels of phosphorylated protein kinase B (PKB/Akt) and phospho-ERK1/2 (p-ERK1/2) in astrocyte culture after oxygen–glucose deprivation. Moreover, the effect of Rd on GLT-1 expression and glutamate uptake can be abolished by PI3K/AKT agonist LY294002 or ERK1/2 inhibitor PD98059. Taken together, our findings provide the first evidence that Rd can promote glutamate clearance by up-regulating GLT-1 expression through PI3K/AKT and ERK1/2 pathways.

Protective effects of ginseng on neurological disorders

“…Ginsenoside Rd increased levels of phosphorylated protein kinase B (PKB/Akt) and phospho-ERK1/2 (p-ERK1/2) and expression of glutamate transporter-1 (GLT-1) in astrocyte cultures after oxygen-glucose deprivation. The effect of Rd on GLT-1 expression was abolished by inhibition of PI3K/AKT or ERK1/2 signaling pathways (Zhang et al, 2013 ). Moreover, total saponins in the leaves of Panax notoginseng reduced H 2 O 2 induced cell death in primary rat cortical astrocytes, likely through nuclear translocation of Nrf2 and upregulation of antioxidant systems including HO-1 and glutathione S-transferase (Zhou et al, 2014b ).…”

Structural characterization of ginseng cyclopeptides and detection of capability to induce apoptosis in gastrointestinal cancer cells

“…For example, both the ginsenoside monomer Rd and ginsenoside Rg1 display excellent anti-tumor potencies in vivo and in vitro. 10,11 However, no studies have focused predominantly on investigating the anti-tumor potency of ginseng cyclopeptides (GCPs). Hence, we isolated GCPs, and explored their antitumor potency and underlying mechanism of action.…”

Ndrg2 deficiency ameliorates neurodegeneration in experimental autoimmune encephalomyelitis

“…) and GLT‐1 (Zhang et al . ) in pathological conditions. Our results were consistent with a recent report that showed that the loss of NDRG2 expression activated PI3K/Akt signaling in cancer cells (Nakahata et al .…”