Ginsenoside Rg1 Exerts Anti-inflammatory Effects via G Protein-Coupled Estrogen Receptor in Lipopolysaccharide-Induced Microglia Activation.

Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson's disease. Ginsenoside Rg1, the most active ingredient of ginseng, has been reported to exert neuroprotective effects via estrogen and glucocorticoid receptors. The present study evaluated the involvement of the G protein-coupled estrogen receptor (GPER) in the anti-inflammatory effects of ginsenoside Rg1 against lipopolysaccharide (LPS)-induced microglia activation in the BV2 microglial cell line and ventral mesencephalic primary microglial culture. The pharmacological blockade and lentivirus-mediated small interfering RNA (siRNA) knockdown of GPER were used to study the underlying mechanism. Rg1 attenuated LPS-induced upregulation of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA and protein levels. The GPER antagonist G15 blocked the inhibitory effects of Rg1 and the GPER-specific agonist G1 on LPS-induced microglia activation. Rg1 mimicked the effects of G1 by inhibiting the LPS-induced activation of nuclear transcription factor-kappa B (NF-κB) and mitogen activated protein kinase signaling pathways, which was also blocked by G15. Moreover, lentivirus-mediated siRNA knockdown of GPER inhibited the anti-inflammatory effects of Rg1. Taken together, our results indicate that GPER is involved in the anti-inflammatory effects of Rg1 against LPS-induced microglia activation. These findings provide a new biological target of Rg1 for the treatment of neuroinflammatory disorders.

Glucocorticoid receptor is involved in the neuroprotective effect of ginsenoside Rg1 against inflammation-induced dopaminergic neuronal degeneration in substantia nigra.

Accumulating clinical and experimental evidence suggests that chronic neuroinflammation is associated with dopaminergic neuronal death in Parkinson's disease (PD). Ginsenoside Rg1, the most active components of ginseng, possesses a variety of biological effects on the central nervous system, cardiovascular system and immune system. The present study aimed to evaluate the protective effects of ginsenoside Rg1 on lipopolysaccharide (LPS)-induced microglia activation and dopaminergic neuronal degeneration in rat substantia nigra (SN) and its potential mechanisms. Treatment with Rg1 could ameliorate the apomorphine-induced rotational behavior in LPS-lesioned rats. GR antagonist RU486 partly abolished the protective effect of Rg1. Rg1 treatment significantly attenuated LPS-induced loss of tyrosin hydroxlase (TH) positive neurons in substantial nigra par compacta (SNpc) and decreased content of dopamine (DA) and its metabolites in striatum of the lesioned side. Meanwhile, Rg1 significantly inhibited LPS-induced microglial activation and production of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and nitric oxide (NO). These effects were abolished by co-treatment with RU486. In addition, Rg1 treatment significantly inhibited the LPS-induced phosphorylation of IκB, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) in the lesioned side of substantial nigra. These effect could be also partly blocked by RU486. Taken together, these data indicate that Rg1 has protective effects on mesencephalic dopaminergic neurons from LPS-induced microglia inflammation. GR signaling pathway might be involved in the anti-inflammatory effect of Rg1.