Ginsenoside Rg3 targets multiple ion channels and receptors. It activates KCNQ1/Kv7.1 K⁺ channels and the γ2 subunit of GABA-A receptors, and inhibits the α10 subunit of nicotinic acetylcholine receptors (nAChRs). The compound enhances cardiac hERG (IKr) and KCNQ (Iks) channel currents by interaction with the channel pore entryway. Ginsenoside Rg3 reversibly inhibits inward Na⁺ peak current (INa) with a voltage-dependent IC₅₀ of 32.2±4.5 μM. It also inhibits the nuclear factor-κB pathway and exhibits COX inhibitory activity.

Ginsenoside Rg3 is a key component in how it affects Na+ channels. Inward Na+ peak current (INa) is reversibly inhibited by ginsenoside Rg3 therapy, with a voltage-dependent IC50 of 32.2±4.5 μM [1]. Ginsenoside Rg3 at 100 μM had an average 65% inhibitory effect on hKv1.4 channel current. Ginsenoside Rg3 has reversible and concentration-dependent actions. The Hill coefficient and IC50 value are 1.59±0.13 and 32.6±2.2 μM, respectively[2]. Ginsenoside Rg3 has the ability to dramatically suppress NF-κB activity, which in turn lowers COX-2 expression. In order to assess the cytotoxicity of ginsenoside Rg3 on A549 cells that had been inflamed by IL-1β, the cells were treated for four hours with IL-1β (10 ng/mL) then for twelve hours with ginsenoside Rg3 at doses ranging from 100 to 900 ng/mL. ..H. The MTT assay was used to examine cell viability. When ginsenoside Rg3 was added to IL-1β-induced inflammatory A549 cells, there was no discernible cytotoxicity (Con) as opposed to PBS-treated cells. We investigated A549 cell inflammation to determine the anti-inflammatory effect of ginsenoside Rg3 on inflammation-induced human lung epithelial cells. stimulated by IL-1β (10 ng/mL) and treated with either 900 nM Rg3 or 5 μM dexamethasone (Dex). Western blot analysis was used to assess NF-κB activation in order to assess the impact of ginsenoside Rg3 therapy on A549 cells. Phosphorylated NF-κB p65/total NF-κB p65 densitometry in Rg3-treated cells was much lower than in IL-1β-stimulated inflammatory A549 cells. NF-κB activation is linked to the relevance of Rg3 therapy in lowering the p-p65/p65 ratio. Moreover, COX-2 expression can be successfully downregulated by ginsenoside Rg3 [3].
In vitro, ginsenoside Rg3 inhibits the palmitate-induced apoptosis of MIN6N8 mouse insulinoma beta-cells through modulating p44/42 MAPK activation. The compound sensitizes human non-small cell lung cancer cells to γ-radiation by targeting the nuclear factor-κB pathway. Ginsenoside Rg3 possesses the ability to inhibit the lung metastasis of tumor cells through inhibition of adhesion, invasion, and anti-angiogenesis activity. The compound also exhibits anti-angiogenic effects in various cell-based assays.

The natural substance ginsenoside Rg3 ((20S)-Rg3) lowers Aβ. For four weeks, APP/PS1 mice received a daily intraperitoneal injection of ginsenoside Rg3 (10 mg/kg/day). Aβ40 and Aβ42 in the brain were significantly reduced after treatment with ginsenoside Rg3, according to an Aβ ELISA assay of brain tissue [4].
In vivo, ginsenoside Rg3 has demonstrated anti-metastatic effects in animal models of cancer. The compound inhibits tumor metastasis by reducing tumor cell adhesion and invasion, and through anti-angiogenic mechanisms. In animal models, ginsenoside Rg3 also exhibits neuroprotective and cardioprotective effects. The compound's ability to modulate ion channels and signaling pathways contributes to its diverse in vivo activities.

Non-cellular enzyme assays for ginsenoside Rg3 involve assessing its effects on ion channel activity using radioligand binding studies with membrane preparations. For Na⁺ channel inhibition, membranes from cells expressing voltage-gated sodium channels are incubated with a radiolabeled sodium channel ligand (e.g., [³H]batrachotoxin) and varying concentrations of ginsenoside Rg3. Binding displacement curves are generated to determine IC₅₀ values. COX inhibition is assessed using standard COX enzyme assays with arachidonic acid as substrate.

In vitro cellular assays for ginsenoside Rg3 involve treating cancer cell lines or neuronal cells with the compound and assessing cell viability, apoptosis, and signaling pathways. Cell viability is measured using MTT or CellTiter-Glo® assays. Apoptosis is assessed by flow cytometry using Annexin V/PI staining or by measuring caspase activity. Ion channel activity is assessed using patch-clamp electrophysiology in cells expressing the relevant channels. NF-κB activity is measured using reporter gene assays or by Western blotting for phosphorylated IκB.

In vivo animal experiments with ginsenoside Rg3 are conducted in mouse xenograft models of cancer to assess anti-tumor and anti-metastatic effects. Tumor-bearing mice are treated with ginsenoside Rg3 via oral or intraperitoneal administration, and tumor growth and metastasis are monitored. In lung metastasis models, the number of metastatic nodules in the lungs is counted. Angiogenesis is assessed using Matrigel plug assays or by measuring microvessel density in tumor tissues.

Anhydrous ginsenoside Rg3 has a molecular weight of 785.01 and a molecular formula of C₄₂H₇₂O₁₃. It is a white to off-white crystalline powder with a purity of ≥98%. The compound is soluble in ethanol, DMSO, and other organic solvents, but poorly soluble in water. It is typically stored at -20°C, protected from light and moisture. The compound is stable under recommended storage conditions.

Ginsenoside Rg3 is generally well-tolerated at therapeutic doses. In preclinical studies, it has demonstrated a favorable safety profile with low acute toxicity. The compound is a natural product and has been used in traditional medicine for centuries. Standard laboratory safety precautions should be followed when handling the compound. It may cause skin, eye, and respiratory irritation.

[1]. A role for the carbohydrate portion of ginsenoside Rg3 in Na+ channel inhibition. Mol Cells. 2005 Feb 28;19(1):137-42.

[2]. Ginsenoside Rg3 inhibits human Kv1.4 channel currents by interacting with the Lys531 residue. Mol Pharmacol. 2008 Mar;73(3):619-26.

[3]. Anti-Inflammatory Effects of Ginsenoside Rg3 via NF-κB Pathway in A549 Cells and Human Asthmatic Lung Tissue. J Immunol Res. 2016;2016:7521601.

[4]. Modulation of lipid kinase PI4KIIα activity and lipid raft association of presenilin 1 underlies γ-secretase inhibition by ginsenoside (20S)-Rg3. J Biol Chem. 2013 Jul 19;288(29):20868-82.

(20S)-Ginsenoside Rg3 is a ginsenoside found in ginseng (Panax ginseng) and Japanese ginseng (Panax japonicus var. major). It belongs to the dammarane type, with its 3β, 12β, and 20 prothiophosphate sites replaced by hydroxyl groups. Specifically, the 3-hydroxyl group is converted to the corresponding β-D-glucopyranosyl-β-D-glucopyranoside, and a double bond is introduced at positions 24-25. It possesses apoptosis-inducing, antitumor, plant metabolite, and angiogenesis-regulating effects. It is a ginsenoside, a tetracyclic triterpenoid, and a glycoside. Its function is related to (20S)-protopanaxadiol. It is derived from the hydride of dammarane. Ginsenoside Rg3 has been reported to exist in Panax notoginseng, ginseng, and other organisms with relevant data.
20(S)-Ginsenoside Rg3 (CAS 14197-60-5) is a major bioactive component of Panax ginseng with diverse pharmacological activities. It targets multiple ion channels including KCNQ1/Kv7.1 K⁺ channels, GABA-A receptors, nAChRs, and voltage-gated Na⁺ channels (IC₅₀ = 32.2±4.5 μM). Ginsenoside Rg3 exhibits anti-cancer, anti-angiogenic, and anti-metastatic effects. The compound is available from various commercial suppliers for research applications.

C42H72O13

785.025

784.497

14197-60-5

(20R)-Ginsenoside Rg3;38243-03-7

9918693

White to off-white solid powder

1.3±0.1 g/cm3

885.0±65.0 °C at 760 mmHg

315-318°C

489.0±34.3 °C

0.0±0.6 mmHg at 25°C

1.594

5.27

9

13

10

55

1370

20

CC(=CCC[C@@](C)([C@H]1CC[C@@]2([C@@H]1[C@@H](C[C@H]3[C@]2(CC[C@@H]4[C@@]3(CC[C@@H](C4(C)C)O[C@H]5[C@@H]([C@H]([C@@H]([C@H](O5)CO)O)O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O)C)C)O)C)O)C

RWXIFXNRCLMQCD-JBVRGBGGSA-N

InChI=1S/C42H72O13/c1-21(2)10-9-14-42(8,51)22-11-16-41(7)29(22)23(45)18-27-39(5)15-13-28(38(3,4)26(39)12-17-40(27,41)6)54-37-35(33(49)31(47)25(20-44)53-37)55-36-34(50)32(48)30(46)24(19-43)52-36/h10,22-37,43-51H,9,11-20H2,1-8H3/t22-,23+,24+,25+,26-,27+,28-,29-,30+,31+,32-,33-,34+,35+,36-,37-,39-,40+,41+,42-/m0/s1

(2S,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-4,5-dihydroxy-2-[[(3S,5R,8R,9R,10R,12R,13R,14R,17S)-12-hydroxy-17-[(2S)-2-hydroxy-6-methylhept-5-en-2-yl]-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-6-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol

VN 10040; VN10040; Ginsenoside RG3

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~127.39 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)