Neuroprotective Effects Of Rg1 Research Articles

Rg1 exerts protective effect in CPZ-induced demyelination mouse model via inhibiting CXCL10-mediated glial response.

Myelin damage and abnormal remyelination processes lead to central nervous system dysfunction. Glial activation-induced microenvironment changes are characteristic features of the diseases with myelin abnormalities. We previously showed that ginsenoside Rg1, a main component of ginseng, ameliorated MPTP-mediated myelin damage in mice, but the underlying mechanisms are unclear. In this study we investigated the effects of Rg1 and mechanisms in cuprizone (CPZ)-induced demyelination mouse model. Mice were treated with CPZ solution (300 mg· kg-1· d-1, ig) for 5 weeks; from week 2, the mice received Rg1 (5, 10, and 20 mg· kg-1· d-1, ig) for 4 weeks. We showed that Rg1 administration dose-dependently alleviated bradykinesia and improved CPZ-disrupted motor coordination ability in CPZ-treated mice. Furthermore, Rg1 administration significantly decreased demyelination and axonal injury in pathological assays. We further revealed that the neuroprotective effects of Rg1 were associated with inhibiting CXCL10-mediated modulation of glial response, which was mediated by NF-κB nuclear translocation and CXCL10 promoter activation. In microglial cell line BV-2, we demonstrated that the effects of Rg1 on pro-inflammatory and migratory phenotypes of microglia were related to CXCL10, while Rg1-induced phagocytosis of microglia was not directly related to CXCL10. In CPZ-induced demyelination mouse model, injection of AAV-CXCL10 shRNA into mouse lateral ventricles 3 weeks prior CPZ treatment occluded the beneficial effects of Rg1 administration in behavioral and pathological assays. In conclusion, CXCL10 mediates the protective role of Rg1 in CPZ-induced demyelination mouse model. This study provides new insight into potential disease-modifying therapies for myelin abnormalities.

Akt/Nrf2 Activated Upregulation of Heme Oxygenase-1 Involves in the Role of Rg1 Against Ferrous Iron-Induced Neurotoxicity in SK-N-SH Cells

Iron accumulation is considered to be involved in the pathogenesis of Parkinson's disease (PD). Our previous studies have observed that Rg1, a major pharmacologically active ingredient from Ginseng, could protect dopaminergic neurons by reducing nigral iron levels through regulating the expression of iron transporters in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice. The aim of this study is to investigate other mechanism involved in the cytoprotection of Rg1 against iron-induced neurotoxicity in human neuroblastoma SK-N-SH cells. Significant rescue of Rg1 on cell viability against 100μM ferrous iron-induced neurotoxicity was observed. Upregulation of heme oxygenase-1 (HO-1) and Cu-Zn superoxide dismutase (Cu/Zn SOD) were observed in Rg1 pretreated group. Moreover, Rg1 pretreatment induces Nrf2 nuclear translocation, which is upstream of HO-1 expression, and activated PI3K/Akt pathway was also observed in Rg1 pretreated group. This could antagonize iron-induced increase in intracellular reactive oxygen species and decrease in mitochondrial transmembrane potential. These results suggest that the neuroprotective effects of Rg1 against iron toxicity are attributed to the anti-oxidative properties by activating Akt/Nrf2 pathway and increasing Nrf2-induced expression of HO-1 and Cu/Zn SOD.

Ginsenoside Rg1 protection against β-amyloid peptide-induced neuronal apoptosis via estrogen receptor α and glucocorticoid receptor-dependent anti-protein nitration pathway

Ginsenoside Rg1 (Rg1) acts as a neuroprotective agent against various insults, however, the underlying mechanism has not been fully elucidated yet. Here, we report that Rg1 protects primary rat cerebrocortical neurons against β-amyloid peptide25–35 (Aβ25–35) injury via estrogen receptor α (ERα) and glucocorticoid receptor (GR)-dependent anti-protein nitration pathway. In primary rat cerebrocortical neuron cultures under basal conditions, Rg1 leads to nuclear translocation of ERα and GR, induces related responsive gene PR, pS2 and MKP-1, SGK transcription. Meantime, Rg1 also increases the basal level of ERK1/2 phosphorylation. In the presence of toxic level of Aβ25–35, Rg1 maintains ERK1/2 phosphorylation, attenuates iNOS expression, NO production, and inhibits NF-κB nuclear translocation, protein nitration and cell death. The antiapoptotic effects of Rg1 via both ERα and GR were abolished by small interfering RNAs (siRNA). ERK1/2 phosphorylation inhibitor U0126 can block downstream iNOS expression and NO generation. Interestingly, the anti-protein nitration effect of Rg1 is well matched with ERα and GR activation, although its anti-ROS production effect is in an ERα- and GR-independent manner. These results suggest that Rg1 ameliorates Aβ25–35-induced neuronal apoptosis at least in part by two complementary ERα- and GR-dependent downstream pathways: (1) upregulation of ERK1/2 phosphorylation followed by inhibiting iNOS expression, NO generation and protein tyrosine nitration. (2) reduction NF-κB nuclear translocation. These data provide new understanding into the mechanisms of Rg1 anti-apoptotic functions after Aβ25–35 exposure, suggesting that ERα and GR-dependent anti-protein tyrosine nitration pathway might take an important role in the neuroprotective effect of Rg1.

Rg1 protects iron‐induced neurotoxicity through antioxidant and iron regulatory proteins in 6‐OHDA‐treated MES23.5 cells

Ginsenoside-Rg1 is one of the pharmacologically active components isolated from ginseng. It was reported that Rg1 protected dopamine (DA) neurons in 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) models in vivo and in vitro. Our previous study also demonstrated that iron accumulation was involved in the toxicity of 6-OHDA. However, whether Rg1 could protect DA neurons against 6-OHDA toxicity by modulating iron accumulation and iron-induced oxidative stress is not clear. Therefore, the present study was carried out to elucidate this effect in 6-OHDA-treated MES23.5 cells and the possible mechanisms were also conducted. Findings showed Rg1 restored iron-induced decrease in mitochondrial transmembrane potential in MES23.5 cells, and increased ferrous iron influx was found in 6-OHDA-treated cells. Rg1 pretreatment could decrease this iron influx by inhibiting 6-OHDA-induced up-regulation of an iron importer protein divalent metal transporter 1 with iron responsive element (DMT1 + IRE). Furthermore, findings also showed that the effect of Rg1 on DMT1 + IRE expression was due to its inhibition of iron regulatory proteins (IRPs) by its antioxidant effect. These results suggested that the neuroprotective effect of Rg1 against iron toxicity in 6-OHDA-treated cells was to decrease the cellular iron accumulation and attenuate the improper up-regulation of DMT1 + IRE via IRE/IRP system. This provides new insight to understand the pharmacological effects of Rg1 on iron-induced degeneration of DA neurons.

Rg1 reduces nigral iron levels of MPTP-treated C57BL6 mice by regulating certain iron transport proteins

Elevated iron levels in the substantia nigra (SN) participate in neuronal death in Parkinson's disease, in which the misregulation of iron transporters such as divalent metal transporter (DMT1) and ferroportin1 (FP1) are involved. Our previous work observed that nigral iron levels were increased in MPTP-treated mice and Ginsenoside Rg1 which is one of the main components of ginseng, had neuroprotective effects against MPTP toxicity. Whether Rg1 could reduce nigral iron levels to protect the dopaminergic neurons? And whether its neuroprotective effect is achieved by regulating certain iron transporters? The present studies showed that Rg1 pre-treatment increased the dopamine and its metabolites contents in the striatum, as well as increased tyrosine hydroxylase expression in the SN. Further experiments observed that Rg1 pre-treatment substantially attenuated MPTP-elevated iron levels, decreased DMT1 expression and increased FP1 expression in the SN. These results suggest that the neuroprotective effect of Rg1 on dopaminergic neurons against MPTP is due to the ability to reduce nigral iron levels, which is achieved by regulating the expressions of DMT1 and FP1.