TABLE 1.
Summary of effects and mechanisms of ginseng and ginsenosides in vitro and in vivo models.
| Gensing and gensinosides | Content of ginsenosides in panax ginseng | Animals/Cells and Dosage | Model | Mechanisms | Effects | References |
|---|---|---|---|---|---|---|
| KRG | C57BL/6 mice, 100 mg/kg | HI | Nrf2↑ | Antioxidant | Liu et al. (2020) | |
| AQP4↓ | ||||||
| KRG | C57BL/6 mice, 100 mg/kg | HI | NQO1, HO1, SOD2, Gpx1, IL-10↑ | Antioxidant, anti-inflammation | Liu et al. (2019b) | |
| IL-1β, iNOS↓ | ||||||
| KRG | C57BL/6 mice, 100 mg/kg | pdMCAO | Nrf2↑ | Oxidative stress, inflammation, improve long-term recovery | Liu et al. (2019a) | |
| AQP4↓ | ||||||
| KRG | C57BL/6 mice, 100 mg/kg | pdMCAO | NQO1, HO1, SOD2, Gpx1↑ | Antioxidant, attenuate acute sensorimotor deficits, improve long-term functional recovery | Liu et al. (2018b) | |
| Nrf2 pathway | ||||||
| RGE | C57BL/6 mice, 360 mg/kg | MCAO | ASK1, ROS, TUNEL↓ | Oxidative stress, apoptosis | Cheon et al. (2013) | |
| KRG | SD rats, 100 mg/kg | MCAO/R | MDA↑ | Antioxidant | Ban et al. (2012) | |
| GPx, SOD, CAT↓ | ||||||
| BG | SD rats, 100 or 400 mg/kg | MCAO | Cholinergic immunoreactivity, NADPH-d↑ | Improve learning and memory | Park et al. (2011a) | |
| KRG | SD rats, 100 mg/kg | tMCAO | TNF-α, IL-1β, IL-6↓ | Inflammation | Lee et al. (2011) | |
| PGE | Wistar rats, 200 mg/kg | TGCI | SOD, GPx↑ | Antioxidant | Kim et al. (2009) | |
| MDA↓ | ||||||
| KGT | Swiss albino rat, 350 mg/kg | MCAO | GSH, GR, CAT, GST, GPx, SOD↑ | Antioxidant | Shah et al. (2005) | |
| LPO↓ | ||||||
| GTS | Wistar rats, 25 mg/kg | MCAO | BrdU+/NeuN+↑ | Neurogenesis | Zheng et al. (2011) | |
| Rd | 0.07 ± 0.03%Park et al. (2013) | C57BL/6 mice, 10, 20, 40 mg/kg | MCAO/R | miR-139-5p, Nrf2↑ | Pyroptosis | Yao et al. (2022) |
| 0.07–0.19%Chen et al. (2019b) | Cortical neuron, 5, 10, 20 μM | OGD/R | NLRP3, ASC, Caspase 1 p20, and GSDMD-N, FoxO1, Keap1, ROS, TXNIP↓ miR-139-5p/FoxO1/Keap1/Nrf2 axis | |||
| Rd | SD rats, 30 mg/kg | MCAO | NF-κB, MMP-9↓NF-κB/MMP-9 pathway | BBB inflammation | Zhang et al. (2020b) | |
| Rd | SD rats, 10 mg/kg | MCAO | P-NR2b at Ser-1303, calcineurin↓ | Excitotoxicity | Zhang et al. (2020a) | |
| Cortical neurons, 0 μM, 3 μM, 10 μM, 100 μM | OGD | |||||
| Rd | C57BL/6 J mice, 10 or 30 mg/kg | CCH | BDNF↑ caspase-3, Ac-H3, HDAC2↓ | Epigenetic modulation apoptosis | Wan et al. (2017) | |
| Neuronal Cell, 0.1, 1.0, and 10 μM | OGD/R | |||||
| Rd | SD rats, 50 mg/kg | MCAO | NR2B, P- Ser-1303, P-Tyr-1472, P- Ser-1480↓ | Neuroprotection | Xie et al. (2016) | |
| Cortical neurons, 10 μM | OGD | |||||
| Rd | SD rats, 10 mg/kg | MCAO | IL-1α, IL-1β, IL-6, IL-10, IL-18, TNF-α, IFN-γ, IκBα, p65, NF-κB↓ | Inflammation | Zhang et al. (2016) | |
| BV2 cells, 10 μM | OGD | |||||
| Rd | SD rats, 30 mg/kg | MCAO | NEIL1, NEIL3 ↑ mtDNA and nDNA damages, caspase-3, TUNEL↓ | Attenuate DNA damage, apoptosis | Yang et al. (2016) | |
| Rd | PC12 cells, 0.1, 1, 10, 50 or 100 µm | GAP-43, ERK1/2, AKT↑ MAPK/ERK and PI3K/AKT pathways | Neurite outgrowth, neuronal repair | Wu et al. (2016a) | ||
| Rd | SD rats, 1, 2.5, and 5 mg/kg | MCAO | BrdU/DCX, Nestin/GFAP, VEGF, BDNF, pAkt, pERK↑ PI3K/Akt and ERK1/2 pathways | Neurogenesis | Liu et al. (2015) | |
| PC12 cells, 25, 50, and 100 μmol/L | OGD | |||||
| Rd | SD rats, 30 and 10 mg/kg Neuron cells, 10 μM | MCAO | PKB/AKT↑ | Attenuates tau protein, reduce sequential cognition impairment | Zhang et al. (2014) | |
| OGD | ptau, GSK-3β↓ PI3K/AKT/GSK-3β pathway | |||||
| Rd | SD rats, 30 mg/kg | MCAO | GLT-1, p-PKB/Akt, p-ERK1/2↑ | Glutamate clearance | Zhang et al. (2013) | |
| Astrocytes, 10 and 50 μM | OGD | glutamate↓ | ||||
| Rd | SD rats, 10 mg/kg | MCAO | NF-κB p65, PARP-1 ↓ | Inflammation, apoptosis | Hu et al. (2013) | |
| Rd | Hippocampal neurons, 0.1, 1, 10 μM | Glutamate-induced | Ca2+ Influx, TUNEL and caspase-3↓ | Ca2+ Influx | Zhang et al. (2012a) | |
| Rd | SD rats, 10 mg/kg | MCAO | ASIC2a↑ | Ca2+ Influx | Zhang et al. (2012b) | |
| TRPM7, ASIC1a↓ | ||||||
| Rd | SD rats, 50 mg/kg | MCAO | ROS, CytoC, AIF↓ | Mitochondrial protection, energy restoration, inhibition of apoptosis | Ye et al. (2011d) | |
| Rd | SD rats, 0.1–200 mg/kg | MCAO | iNOS and COX-2↓ | Oxidative, inflammatory | Ye et al. (2011c) | |
| Rd | SD rats, 10–50 mg/kg | MCAO | BBB permeability↑ | Wider therapeutic window | Ye et al. (2011a) | |
| Rd | C57BL/6 mice, 10–50 mg/kg | MCAO | CAT, SOD2, GPX, GST, GSH/GSSG, complexes I-IV↑ ROS↓ | Redox imbalance, oxidative damage, mitochondrial function | Ye et al. (2011b) | |
| Rd | Cortical neurons, 1, 3, 10, 30 and 60 μM | Glutamate-induced | caspase 3, Ca2+ influx↓ | Apoptosis | Li et al. (2010) | |
| Rd | Hippocampal neurons, 0.1–10 μM | OGD | GPX, SOD, CAT↑ MDA, GSH, GSSG, ROS↓ | Oxidative stress | Ye et al. (2009) | |
| Rb1 | 0.11 ± 0.02%Park et al. (2013) | C57BL/6 mic, 50 mg/kg | dMCAO | GAP43, BDA, cAMP, PKA, pCREB↑ cAMP/PKA/CREB Pathway | Axonal regeneration, motor functional recovery | Gao et al. (2020b) |
| 0.29–2.0%Chen et al. (2019b) | ||||||
| Rb1, Rg1 | Astrocyte cultures | OGD/R | CAT, complexes I-V, ATP↑ | Mitochondrial oxidative | Xu et al. (2019) | |
| Rb1, 2, 5, 10 µM | ROS↓ | |||||
| Rg1, 2, 5, 10 µM | ||||||
| Rb1, Rh2, Rg1, Rg3, Rg5, Re | PC12 cells Rb1, 50 μg/ml Rh2, 0.5 μg/ml Rg1, 5 μg/ml Rg3, 20 μg/ml Rg5, 100 μg/ml Re, 5 μg/ml | CoCl2-induced | ROS, TLR4, MyD88, SIRT1, P65, IL-1β, TNF-α, IL-6↓ | Apoptosis, mitochondrial membrane potential, inflammation | Cheng et al. (2019) | |
| Rb1 | SD rats, 50 or 100 mg/kg SH-SY5Y cells, 10 μmol/L | Microperfusion of Glu and CaCl2 OGD/R | P-Akt, P-mTOR↑ P-PTEN↓P-AKT/P-mTOR pathway | Neuroprotection, microenvironment | Guo et al. (2018) | |
| Rb1 | Wistar rats, 50, 10, 200 mg/kg | MCAO | caspase-3, caspase-9, HMGB1, NF-κB, TNF-α, IL-6, NO↓ | Apoptosis, inflammation | Liu et al. (2018a) | |
| Rb1 | C57BL/6 J mice, 0.5, 1, 5 or 10 mg/kg | MCAO | GSH↑ | Antioxidant | Dong et al. (2017) | |
| MDA, NO, ROS, NOX-1, NOX-4, NADPH, pERK1/2↓ | ||||||
| Rb1 | ICR mice, 5, 20 or 40 mg/kg | MCAO | MMP-9, NOX-4 ↓ | BBB | Chen et al. (2015) | |
| Rb1 | Microglial cell, 100 μg/ml | H2O2-induced | TNF-α, NO, O2-↓ | Apoptosis | Ke et al. (2014) | |
| Rb1 | SH-SY5Y cells, 1.0, 10 and 100 µM | OGD | p-Akt↑ | Aautophagy | Luo et al. (2014) | |
| LC3II, Beclin1 ↓PI3K/Akt Pathway | ||||||
| Rb1 | SD rats, 100 mg/kg | MCAO | BDNF, GAP-43, NF↑ | Neuroprotection | Jiang et al. (2013) | |
| IL-1, TNF-α↓ | ||||||
| Rb1 | SD rats, 12.5 mg/kg | MCAO | NF-κB/p65, IKK-α, IκB-α, TNF-α, IL-6↓ | Inflammation | Zhu et al. (2012) | |
| Rb1 | SD rats, 12.5 mg/kg | MCAO | LC3, Beclin 1↓ | Autophagy | Lu et al. (2011) | |
| Rb1 | Wistar rats, 40 mg/kg | MCAO | BDNF↑ caspase-3↓ | Neurogenesis | Gao et al. (2010) | |
| Rb1 | Cynomolgus monkeys, 300 μg/kg | TSM | NeuN↑ | Neuroprotection | Yoshikawa et al. (2008) | |
| TUNEL, GFAP↓ | ||||||
| Rb1 | SHR-SP rats, 20 μg/kg | MCAO | VEGF, Bcl-xL↑ | Neuroprotection | Sakanaka et al. (2007) | |
| Rb1 | Wistar rats, 40 mg/kg | MCAO | GDNF, Bcl-2↑ bax↓ | Apoptotic | Yuan et al. (2007) | |
| Rb1 | SHR-SP rats, 20 μg/kg | MCAO | Bcl-xL↑ | Apoptotic | Zhang et al. (2006) | |
| Rb1 | SHR-SP rats, 20 μg/kg | MCAO | Infarcted area↓ scavenging free radicals | neuroprotection | Zhang et al. (1998) | |
| Rb1 | Mongolian gerbils, 80 μg/kg | TFI | Hippocampal blood flow↑ scavenging free radicals | neuroprotection | Lim et al. (1997) | |
| Rg1 | 0.27 ± 0.04%Park et al. (2013) | SD rats, 40 mg/kg | MCAO | Bcl2 ↑ | ER, apoptosis | Gu et al. (2020) |
| 0.32–1.55%Chen et al. (2019b) | Bax, TUNEL, p-PERK, p-eIF2, ATF4↓ PERK-eIF2-α-ATF4 signaling pathway | |||||
| Rg1 | SD rats, 50 mg/kg | MCAO | Glycolysis or gluconeogenesis, amino acid metabolism, lipid metabolism↓ | Energy metabolism, amino acids metabolism, lipids metabolism | Gao et al. (2020a) | |
| Rg1 | SD rats, 20 mg/kg | tMCAO OGD/R | Nrf2, ARE, HO-1, NQO-1, GCLC, GCLM↑ miR-144 ↓ miR-144/Nrf2/ARE pathway | Oxidative stress | Chu et al. (2019) | |
| PC12 cells, 0.01–1 μmol/L | ||||||
| Rg1 | SD rats, 10, 20, or 40 mg/kg | MCAO | p-IκBα, P65, IL-6, IL-1β, TNF-α, IFN-γ↓ | Inflammation | Zheng et al. (2019) | |
| Rg1 | C57BL/6 mice,10, 20 or 40 mg/kg hCMEC/D3 cells,0.1–1,000 μM | dMCAO OGD | BrdU+/CD31+, BrdU+/GFAP+, VEGF, HIF-1α, p-Akt, p-mTOR↑ PI3K/Akt/mTOR signaling pathway | Angiogenesis | Chen et al. (2019a) | |
| Rg1 | C57BL/6 mice, 20, 40 mg/kg | MCAO | BDNF↑ IL-1β, TNF-α, IL-6, Glu, Asp↓ | Neuroprotection | Wang et al. (2018b) | |
| Rg1 | SD rats, 6 mg/kg BV2, 8 μg/ml | MCAO OGD | miR-155-5p↓ | Neuroprotection | Wang et al. (2018a) | |
| Rg1 | SD rats, 30 or 60 mg/kg | MCAO | SOD, CAT, PPARγ↑ | Antioxidative, anti-Inflammatory | Li et al. (2017a) | |
| Cortical neurons, 30 or 60 μM | OGD | MPO, TNF-α, IL-6↓ | ||||
| Rg1 | NSCs, 0.01–50 µM | OGD | Bcl-2↑ | Apoptosis | Li et al. (2017b) | |
| Caspase3, Bax, p-p38, p-JNK2↓ | ||||||
| Rg1 | SD rats, 40 mg/kg | MCAO | PAR-1↓ | BBB permeability | Xie et al. (2015) | |
| Rg1 | SD rats, 20, 40 or 60 mg/kg | MCAO | PPARγ, HO-1, bcl-2↑ caspase-3, caspase-9, IL-1β, TNF-α, HMGB1, RAGE↓ PPARγ/Heme oxygenase-1 (HO-1) signaling | Inflammation, apoptosis | Yang et al. (2015) | |
| Rg1 | SD rats, 30, 60 mg/kg | MCAO | Regulate systemic metabolic | Neuroprotection | Lin et al. (2015) | |
| Rg1 | Hippocampal neurons, 5, 20, 60 mM | OGD | Calcium influx↓ nNOS↑ | Neuroprotection | He et al. (2014) | |
| Rg1 | BALB/c mice, 20 or 40 mg/kg | MCAO | mitochondrial membrane potential↑ | Apoptosis Ca2+ overload | Sun et al. (2014) | |
| Astrocytes, 10 µM | H2O2-induced | Ca2+, ROS↓ | ||||
| Rg1 | SD rats, 20 mg/kg | MCAO | AQP4↓ | BBB | Zhou et al. (2014) | |
| Rg1 | PC12 cells, 0.1–10 uM | H2O2- induced | Akt, ERK1/2 ↑ p-IkBα, p-IKKβ, p65↓ NF-kB pathway | Oxidative stress | Liu et al. (2011) | |
| Rg1 | SD rats, 20 mg/kg | MCAO | Ca2+↓ | Neuroprotection | Zhang et al. (2008b) | |
| Hippocampal neurons, 110,100 uM | OGD | NMDA receptors and L-type voltage-dependent Ca2+ channels | ||||
| Rg1 | Mongolian gerbils, 5 and 10 mg/kg | MCAO | Brdu↑ | Neurogenesis cell proliferation | Shen and Zhang, (2003) | |
| Rg2 | 0.06 ± 0.04%Park et al. (2013) | SD rats, 2.5, 5 and 10 mg/kg | MCAO | BCL-2, P53↑ | Apoptosis | Zhang et al. (2008a) |
| 0.01–0.09%Chen et al. (2019b) | BAX, HSP70↓ | |||||
| Rg3 | 0.05 ± 0.04%Park et al. (2013) | SD rats, 20 mg/kg | MCAO/R | 22 differentially expressed miRNAs 415 differentially expressed mRNAs cGMP-PKG, cAMP and MAPK signaling pathways | Neuroprotection | Zhang et al. (2022) |
| 0.001–0.003%Chen et al. (2019b) | ||||||
| Rg3 | SD rats, 20 mg/kg | MCAO/R | 239 differentially expressed lncRNAs 538 differentially expressed mRNAs TNF, NF-κB, cytokine, and other receptor signaling pathways | Neuroprotection | Yang et al. (2022) | |
| Rg3 | SH-SY5Y cells, 1, 5, 25, 125 μmol/L | OGD/R | Bcl-2↑ | Apoptosis | He et al. (2017) | |
| Bax, cleaved caspase-3↓ | ||||||
| Rg3 | SD rats, 10 and 20 mg/kg | MCAO | calpain I, caspase-3, TUNEL↓ | Neuroprotection, apoptosis | He et al. (2012) | |
| Rg3 | Mitochondria, 2–16 μM | Ca2+, H2O2 induced | ATP, respiratory control ratio ↑ | Neuroprotection | Tian et al. (2009) | |
| MPTP↓ | ||||||
| Rg3 | Wistar rats, 10 and 5 mg/kg | MCAO | MDA, ATP ↑ | Lipid peroxides, oxidative stress, energy metabolism | Tian et al. (2005) | |
| SOD, GSH-Px ↓ | ||||||
| Re | 0.22 ± 0.03%Park et al. (2013) | SD rats, 5, 10 or 20 mg/kg | MCAO | MDA, H+ -ATPase↓ decrease mitochondrial swelling | Oxidative stress | Chen et al. (2008) |
| 0.44–1.2%Chen et al. (2019b) | ||||||
| Re | Wistar rats, 5, 10, 20 mg/kg | MCAO | SOD, GSH-Px↑ | Oxidative stress | Zhou et al. (2006) | |
| MDA↓ | ||||||
| CK | PC12 cells, 2, 4, 8 μM | OGD/R | p-mTOR↑p-AMPK, p62, Atg7, Atg5, LC3II/I↓ AMPK-mTOR pathway | Autophagy, apoptosis | Huang et al. (2020) | |
| CK | C57BL/6 mice, 30 mg/kg | MCAO | HO-1↑ | Anti-inflammation | Park et al. (2012) | |
| BV2, 25, 50, 75 μM | LPS | IL-6, MCP-1, MMP-3, and MMP-9↓ ROS, MAPKs, NF-κB/AP-1, and HO-1/ARE signaling pathways | ||||
| OA | SD rats, 10, 20 mg/kg | MCAO | Nissl+, NeuN+↑ | Antioxidative | Lin et al. (2021) | |
| SH-SY5Y cells, 10, 20, and 40 µM | OGD/R | GSK-3β, HO-1, ROS, TUNEL ↓ GSK-3β/HO-1 pathway | ||||
| F1 | SD rats, 50 mg/kg | MCAO | MVD, IGF-1/IGF1R↑ IGF-1/IGF1R pathway | Angiogenesis, improve focal cerebral blood perfusion | Zhang et al. (2019) | |
| Rh2 | 0.001–0.006%Chen et al. (2019b) | BV2, 5, 25 μM | LPS and IFN-γ-induced | IL-10↑ | Inflammation | Bae et al. (2006) |
| NO, COX-2, TNF-α, IL-1↓ AP-1 and PKA pathway |
KRG, Korean red ginseng; BG, Black ginseng; KGT, Korean ginseng tea; RGE, Red Ginseng Extract; PGE, Panax ginseng extract; GTS, Ginseng total saponins; GTS, Ginseng total saponins; CK, Compound K; OA, Oleanolic acid; HI, Hypoxia-Ischemia; pdMCAO, permanent distal middle cerebral artery occlusion; tMCAO, transient middle cerebral artery occlusion; MCAO/R, middle cerebral artery occlusion/reperfusion; TGCI, transient global cerebral ischemia; TSM,T hromboembolic stroke model; TFI, transient forebrain ischemia; OGD/R, oxygen-glucose deprivation/reoxygenation; CCH, chronic cerebral hypoperfusion; NSCs, Neural stem cells; ASK1, apoptosis signal-regulating kinase 1; NADPH-d, nicotinamide adenine dinucleotide phosphate-diaphorase; TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1 beta; MDA, malondialdehyde; SOD, superoxide dismutase; GPx, glutathione peroxidase; LPO, lipid peroxidation; GSH, glutathione; GR, glutathione reductase; CAT, catalase; GST, glutathione-S-transferase; Ac-H3, acetylated histone H3; HDAC2, histone deacetylase 2; mtDNA, mitochondrial DNA; ROS, reactive oxygen species; ATP, adenosine triphosphate; HMGB1, High-mobility group box 1; MMP-9, matrix metalloproteinase-9; NOX, nicotinamide adenine dinucleotide phosphate oxidase; HSP70, heat shock protein 70; BBB, blood–brain barrier; ER, endoplasmic reticulum stress; MPTP, mitochondrial permeability transition pore; MVD, microvessel density.