Abstract WP132: Korean Red Ginseng Attenuates Reactive Gliosis and Confers Sustained Neuroprotection against Cerebral Hypoxic-Ischemic Damage in an Nrf2-Dependent Manner

Cerebral ischemia is a devastating disease with a high incidence of death and disability; however, effective therapeutics remain limited. The transcriptional factor Nrf2 has been shown to play a pivotal role in the endogenous defense against brain oxidative stress and inflammation, and therefore represents a promising target for stroke intervention. However, the long-term effects of Nrf2 and the standardized Korean red ginseng (ginseng), a potent Nrf2 natural inducer, on permanent cerebral ischemic damage have not yet been reported. Wildtype (WT) and Nrf2-/- adult mice were pretreated with either vehicle or ginseng, and were subjected to permanent distal middle cerebral artery occlusion (pdMCAO). The infarct volume, the reactive astrocytes and microglia, and the water regulatory protein aquaporin 4 (AQP4) were examined at 28 days after stroke. When compared with the WT matched controls, the Nrf2 disruption significantly enlarged the infarct volume (40.4 ± 10.1%) and exacerbated the progression of reactive gliosis and AQP4 protein levels after pdMCAO. In contrast, ginseng significantly reduced the infarct volume and attenuated the reactive gliosis and AQP4 in the ischemic WT mice (47.3 ± 6.9%), but not in the Nrf2-/- mice (25.5 ± 5.6%). In conclusion, Nrf2 plays an important role in the long-term recovery of permanent cerebral ischemic damage and the neuroprotection of ginseng.

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Abstract TP97: Korean Red Ginseng Ameliorates Cerebral Hypoxic-Ischemic Damage Through the Activation of the Nrf2 Pathway by Preferentially Altering Reactive Astrogliosis

Stroke ◽

10.1161/str.48.suppl_1.tp97 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Lei Liu ◽

Mary K. Vollmer ◽

Morgan W. Carson ◽

Todd J. Sahagian ◽

Hocheol Kim ◽

...

Keyword(s):

Brain Damage ◽

Neuronal Death ◽

Ischemic Damage ◽

Protective Effects ◽

Red Ginseng ◽

Korean Red Ginseng ◽

Neuroprotective Effects ◽

Edema Formation ◽

Ischemic Brain ◽

Nrf2 Pathway

Introduction: Endogenous defense mechanisms by which the brain protects itself against noxious stimuli and recovers from ischemic damage are key targets of stroke research that may ultimately facilitate functional recovery. Multiple evidences indicate that the transcriptional factor Nrf2 plays a vital role in cellular defense against oxidative stress and inflammation, and consequently, targeting Nrf2 has emerged as a promising therapeutic strategy for disease prevention. Korean Red Ginseng (Ginseng), one of the most widely used herbal medicines in the world, has been suggested as one of the most potent Nrf2 activators, thereby making it efficacious against various acute neurological disorders, including stroke. Hypothesis: To evaluate whether Ginseng could exert protective effects against hypoxic-ischemic brain damage and whether Nrf2 activation is pivotal to the various neuroprotective effects of Ginseng. Methods: C57BL/6 WT and Nrf2 knockout mice (10-18 weeks old, n=12-16) were orally administered Ginseng (100mg/kg/d) or vehicle 7d prior to cerebral hypoxic-ischemic damage. At 6 and 24h after stroke, mice were neurologically scored. Brain lesion size and edema formation were measured at 24h. Using immunostaining, we examined which cells appeared to be most preferentially activated in a spatiotemporal pattern by this Nrf2 pathway, in particular, in the early stage of ischemic injury. Based on the results, we are further evaluating the efficacy of inducing the Nrf2 pathway and assess the extended neuroprotective effects of Ginseng at 7d after stroke. Results: Ginseng treatment significantly reduced cerebral infarct size, neuronal death, edema formation and the resultant functional neurological deficits at 24h after stroke (P<0.001); whereas, Nrf2 ablation remarkably attenuated all benefits. Notably, the above protective effects of Ginseng were significantly attenuated in Nrf2 knockouts (P<0.05). In addition, Ginseng treated mice also exhibited reduced neuronal death and delayed severe reactive astrogliosis at 6 and 12h (P<0.05). Conclusion: Our findings indicate a neuroprotective effect of Ginseng against hypoxic-ischemic brain damage, and that Nrf2-dependent cytoprotective responses appear to be more prominent in astrocytes.

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Signaling Pathways Associated with Macrophage-Activating Polysaccharide Isolated from Korea Red Ginseng

Applied Sciences ◽

10.3390/app11157111 ◽

2021 ◽

Vol 11 (15) ◽

pp. 7111

Author(s):

Jie Gao ◽

Sullim Lee ◽

Ji-Hwan Lee ◽

Ki-Sung Kang ◽

Myoung-Sook Shin

Keyword(s):

Nitric Oxide ◽

Raw264.7 Cells ◽

Raw 264.7 Cells ◽

Dependent Manner ◽

Red Ginseng ◽

Health Food ◽

Griess Reagent ◽

Korean Red Ginseng ◽

Concentration Dependent Manner ◽

Tnf Α

Background and Objectives: Korean red ginseng (KRG) is known as an immune-enhancing health food and has been approved by the Korea Food and Drug Administration. We analyzed the immune-enhancing activity of KRG and its polysaccharide (KRG-P) using RAW264.7 murine macrophage cells. Materials and Methods: The protein and mRNA expression levels of IL-6 and TNF-α were measured using ELISA and qRT-PCR, respectively. Nitric oxide levels were measured using the Griess reagent. The phosphorylation and total protein levels of ERK, p38, JNK, p65, and GAPDH were determined by immunoblot assay. Results: The polysaccharide (KRG-P), but not KRG, produced nitric oxide, interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in RAW 264.7 cells. KRG-P increased nitric oxide synthase 2 (NOS2), IL-6, and TNF-α expression in RAW264.7 cells. KRG-P also increased phosphorylation of MAPKs (mitogen-activate protein kinases) including ERK, p38, JNK, and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in a concentration-dependent manner in RAW264.7 cells. Conclusions: The polysaccharide KRG-P is the active component responsible for the immune-enhancing activity of Korean red ginseng and may modulate the systemic immune system in vivo.

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Abstract TP115: Nrf2 Plays an Essential Role in Long-Term Neuroprotection of Ginseng in Permanent Cerebral Ischemia

Stroke ◽

10.1161/str.51.suppl_1.tp115 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Anna Skrobach ◽

Lei Liu ◽

Marie G Kelly ◽

Erika L Wierzbicki ◽

Iana C Escober-Nario ◽

...

Keyword(s):

Cerebral Ischemia ◽

Infarct Volume ◽

Regulatory Protein ◽

Reactive Gliosis ◽

Ischemic Damage ◽

Long Term Effects ◽

Korean Red Ginseng ◽

Cerebral Ischemic ◽

Cerebral Ischemic Damage

Introduction: Cerebral ischemia is a devastating disease with a high incidence of death and disability; however, effective therapeutics remain limited. The transcriptional factor Nrf2 has been shown to play a pivotal role in the endogenous defense against brain oxidative stress and inflammation; therefore, it represents a promising target for stroke intervention. The natural potential Nrf2-inducer ginseng, extracted from the root of Panax ginseng C.A.Meyer, has been widely used in East Asia for thousands of years, exhibiting potent anti-inflammatory and antioxidative properties. However, the long-term effects of Nrf2 and the standardized Korean red ginseng extract (ginseng) on permanent cerebral ischemic damage have not yet been reported. Methods: Wildtype (WT) and Nrf2 –/– adult mice were treated with either vehicle (water) or ginseng for 7 days and subjected to the permanent distal middle cerebral artery occlusion (pdMCAO). The infarct volume, the reactive astrogliosis and microgliosis, and water regulatory protein aquaporin 4 (AQP4) were examined 28 days after the initiation of stroke. Data acquisition and analyses were performed by an observer blinded to the treatment. Results: When compared with the WT matched controls, the Nrf2 disruption significantly enlarged the infarct volume by 40.4±10.1% (n=7 per group; p<0.05), increased levels of reactive gliosis and AQP4 protein after pdMCAO. Interestingly, ginseng significantly reduced the infarct volume and attenuated the reactive gliosis and AQP4 in the ischemic WT mice (47.3±6.9%, n=12; p<0.01), but not in the Nrf2 -/- mice (25.5±5.6%, n=11; p=0.241). Conclusion: Nrf2 plays an important role in the long-term recovery of permanent cerebral ischemic damage and neuroprotection of ginseng.

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Korean Red Ginseng Inhibits Amyloid-β-Induced Apoptosis and Nucling Expression in Human Neuronal Cells

Pharmacology ◽

10.1159/000505592 ◽

2020 ◽

Vol 105 (9-10) ◽

pp. 586-597 ◽

Cited By ~ 1

Author(s):

Suyun Choi ◽

Joo Weon Lim ◽

Hyeyoung Kim

Keyword(s):

Mitochondrial Dysfunction ◽

Neuronal Apoptosis ◽

Neuronal Cells ◽

Neuronal Cell Death ◽

Amyloid Β ◽

Neuronal Cell ◽

Dependent Manner ◽

Red Ginseng ◽

Korean Red Ginseng ◽

Human Neuronal Cells

Introduction: The accumulation of amyloid-β (Aβ) plaque in the brain is a characteristic feature of Alzheimer’s disease (AD) and the cause of fatal oxidative damage to neuronal cells. Korean red ginseng (RG) is used extensively in traditional medicine and is known to have anti-oxidative and anti-inflammatory properties. Objective: This study aims to investigate whether Korean RG extract inhibits Aβ-induced neuronal apoptosis. Methods: Human neuronal cells (SH-SY5Y cells) were stimulated with Aβ (5 μmol/L) and treated with RG dissolved in phosphate-buffered saline (0.2, 2, 20 μg/mL). Results: RG suppressed the reduction of cell viability and the increase in apoptotic factors (Bax/Bcl-2 ratio and caspase-3 activity) in Aβ-treated cells. RG suppressed Aβ-induced increases in intracellular and mitochondrial reactive oxygen species (ROS) levels and mitochondrial dysfunction (determined by low mitochondrial membrane potential and oxygen consumption rate) in a dose-dependent manner. RG inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) activation and expression of the pro-apoptotic gene Nucling in Aβ-treated cells. Conclusion: RG confers protection against neuronal apoptosis by reducing ROS levels and suppressing mitochondrial dysfunction and NF-κB activation, which results in suppression of NF-κB-mediated activation of Nucling expression in Aβ-treated cells. Supplementation with RG may be beneficial for preventing Aβ-induced neuronal cell death associated with AD.

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Reactive Gliosis Contributes to Nrf2-Dependent Neuroprotection by Pretreatment with Dimethyl Fumarate or Korean Red Ginseng Against Hypoxic-Ischemia: Focus on Hippocampal Injury

Molecular Neurobiology ◽

10.1007/s12035-019-01760-0 ◽

2019 ◽

Vol 57 (1) ◽

pp. 105-117 ◽

Cited By ~ 2

Author(s):

Lei Liu ◽

Mary K. Vollmer ◽

Marie G. Kelly ◽

Victoria M. Fernandez ◽

Tyler G. Fernandez ◽

...

Keyword(s):

Dimethyl Fumarate ◽

Reactive Gliosis ◽

Red Ginseng ◽

Korean Red Ginseng ◽

Hypoxic Ischemia

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Evaluation of Red Ginseng-Drug Interaction by CYP450 Induction in High Dose Administration in Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzaa045_050 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 417-417

Author(s):

YounAh Kim ◽

Sumin Choi ◽

Jong-Sup Bae ◽

Sangkyu Lee

Keyword(s):

Drug Interaction ◽

Technology Development ◽

Development Program ◽

Drug Effects ◽

Time Dependent ◽

High Dose ◽

Dependent Manner ◽

Red Ginseng ◽

Korean Red Ginseng

Abstract Objectives Ginseng–drug interactions at high doses of ginseng are poorly understood. Here we observed the possibility of herb–drug interaction between the Korean red ginseng (KRG) extract and cytochrome P450 (CYP) substrates in higher administration. Methods We determined the CYP activities in vivo after orally administration of KRG extract doses of 0.5, 1.0, and 2.0 g/kg for 2 or 4 weeks by monitoring the concentration of five CYP substrates/metabolites in the blood. Results The AUC for OH-midazolam/midazolam catalyzed by CYP3A was increased significantly by the administration of 2.0 g/kg KRG extract for 2 and 4 weeks. CYP3A-catalyzed midazolam 1ʹ-hydroxylation also increased significantly in a dose- and time-dependent manner in the S9 fraction of mouse liver which wasn't related to induction by transcription. Whereas CYP2D-catalyzed dextromethorphan O-deethylation decreased in a dose- and time-dependent manner in vivo. We observed interactions between KRG extract and CYP2D and CYP3A substrates at high KRG doses in mice. Conclusions Based on this result, patients may adhere to a daily recommended dose for ginseng products to avoid adverse drug effects. Funding Sources This work was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry, and Fisheries (IPET) through the Export Promotion Technology Development Program, funded by the Ministry of Agriculture, Food and Rural Affairs (MAFRA, grant number 316,017–3) and the Korea Basic Science Institute (KBSI) National Research Facilities & Equipment Center (NFEC) grant funded by the Korea Government (Ministry of Education) (No. 2019R1A6C1010001).

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