Product name: Ginsenoside Re
Synonym name:
Catalogue No.: BP0662
Cas No.: 52286-59-6
Formula: C₄₈H₈₂O₁₈
Mol Weight: 947.166
Botanical Source: Panax ginseng (ginseng) and Panax japonicus (Japanese ginseng)
Physical Description: White powder
Type of Compound: Triterpenoids

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle

Storage: Store in a well closed container, protected from air and light. Put into refrigerate or freeze for long term storage.
Whenever possible, you should prepare and use solutions on the same day. However, if you need to make up stock solutions in advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20℃. Generally, these will be useable for up to two weeks.

The product could be supplied from milligrams to grams, up to kilograms
Inquire for bulk scale.

Descriptions:
Ginsenoside Re, a main phytosterol of Panax ginseng, inhibits Ca(2+) accumulation in mitochondria during cardiac ischemia/reperfusion, which is attributable to nitric oxide (NO)-induced Ca(2+) channel inhibition and K(+) channel activation in cardiac myocytes, acts as a specific agonist for the nongenomic pathway of sex steroid receptors, and NO released from activated eNOS underlies cardiac K(+) channel activation and protection against ischemia-reperfusion injury, G-Re also exerts antiischemic effect and induces angiogenic regeneration.[1,2]
Ginsenoside Re has anti-diabetic and anti-hyperlipidemic activities ,can improve hyperglycemia and hyperlipidemia through activation of AMPK, and confer beneficial effects on type 2 diabetic patients with insulin resistance and dyslipidemia. [3]
Ginsenoside Re can improve the cognition of streptozotocin-induced diabetic rats,the mechanism is by its anti-inflammation and antioxidation; glycemic control benefits the attenuation of diabetes-associated cognitive decline.[4]
Ginsenoside Re can hyperpolarize HCAECs,and this effect can be reversed by apamin, suggests ginsenoside Re increases HCAEC outward current via SKCa channel activation, and NSC channel is not involved.[5]
Ginsenoside Re increases the proliferation of CD4 + T cells with decreases cell death, and enhances viability of CD4 + T cells through the regulation of IFN-γ-dependent autophagy activity.[6]
Ginsenoside Re exhibits potent neuroprotective effects against neuroinflammation in a murine model of ALS, ginsenoside Re treatment can reduce the loss of motor neurons and active-microglia-related expression of Iba-1 in the spinal cord of symptom.

References:
[1] Furukawa T, Bai C X, Kaihara A, et al. Mol Pharmacol, 2006, 70(6):1916-24.
[2] Peng L, Sun S, Xie L H, et al. Cardiovasc Ther , 2012, 30(4):e183–e188.
[3] Quan H Y, Yuan H D, Jung M S, et al. Int J of Mol Med, 2012, 29(1):73-80.
[4] Liu Y W, Zhu X, Li W, et al. Pharmacol Biochem, 2012, 101(1):93-98.
[5] Sukrittanon S, Watanapa W B, Ruamyod K. Life Sci, 2014, 115(1–2):15-21.
[6] Son Y M, Kwak C W, Lee Y J, et al. Int Immunopharmaco, 2010, 10(5):626-631.
[7] Cai M, Yang E J. Am J Chinese Med, 2016, 44(2):401-413.
[8] Huang X, Liang T. Chinese Medicine Modern Distance Education of China, 2011, 09(21):131-132.

HPLC of Ginsenoside Re

HNMR of Ginsenoside Re

Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

Ginsenoside Re is a plant of the Panax genus in the Araliaceae family, such as ginseng Panax ginseng Sanqi Panax notoginseng An important dammarane type tetracyclic triterpenoid saponin extracted from (etc.), with a CAS number of 52286-59-6. As one of the main members of the ginsenoside Rb group, ginsenoside Re has a long history of application in traditional medicine, and modern pharmacological research has gradually revealed its biological activities in various aspects such as neuroprotection, anti-inflammatory, and cardiovascular regulation. Especially with the acceleration of global aging process, the incidence rate of neurodegenerative diseases such as Alzheimer's disease (AD) is increasing year by year, and finding safe and effective neuroprotective agents has become a research hotspot. Ginsenoside Re has attracted widespread attention in the pharmacology community due to its significant neuroprotective potential, as it can reduce levels of β - amyloid (A β) and inhibit neuroinflammation. This article aims to systematically review the chemical structure, plant origin, pharmacological activity, molecular mechanism of action, pharmacological evaluation, and clinical application prospects of ginsenoside Re, in order to provide comprehensive scientific references for the in-depth research and development of this natural product.

Chemical structure and physicochemical properties

Ginsenoside Re belongs to the original panaxatriol type saponin, with a molecular formula of C48H82O18 and a molecular weight of 947.1660. Its basic skeleton is a damaane type tetracyclic triterpene, with sugar groups connected at positions C-3 and C-20, respectively. Specifically, its C-3 position is connected to a glucose group (Glc), while its C-20 position is connected to a disaccharide chain composed of rhamnose (Rha) and glucose (Glc) (Rha (1 → 6) Glc). This unique glycosylation pattern has a decisive impact on its biological activity and physicochemical properties.

In terms of physical and chemical properties, the theoretical lipid water partition coefficient (LogP) of ginsenoside Re is 2.3919, indicating that it has a certain lipophilicity, but not high lipid solubility. Its topological polar surface area (TPSA) is as high as 298.1400 Å ², which is mainly attributed to the abundant hydroxyl and sugar structures in the molecule, resulting in strong polarity. The calculated water solubility is about 0.1336 mg/mL, belonging to the category of slightly soluble to poorly soluble, which poses challenges for its oral absorption and formulation development. These parameters collectively determine the basic behavior of ginsenoside Re in vivo: a moderate LogP value suggests that it may have some membrane permeability, but its extremely high TPSA and low water solubility limit its transmembrane diffusion efficiency, especially its ability to pass through the blood-brain barrier (BBB) is predicted to be "low", which constitutes a major obstacle to its central nervous system protective effect. In addition, preliminary pharmacological screening showed no significant inhibitory effect on hERG potassium channels (hERG inhibition: No), and the Ames test result was 0.0, suggesting that it may not have mutagenicity and potential cardiac toxicity risks, and has a good safety basis.

Plant sources and extraction methods

Ginsenoside Re is mainly present in various plants of the Panax genus in the Araliaceae family and is one of its characteristic active ingredients.
1. Main source：
* Ginseng（Panax ginseng C. A. Mey.）Mainly produced in Northeast China, South Korea, and other regions, ginsenoside Re is an important saponin component in its roots, stems, and leaves, and its content varies depending on the place of origin, growth period, and location.
* Sanqi（Panax notoginseng (Burk.) F. H. Chen）As a traditional precious medicinal herb, the content of ginsenoside Re in Panax notoginseng is also relatively abundant, which is one of the material bases for its functions of promoting blood circulation, removing blood stasis, and neuroprotection.
* American ginseng（Panax quinquefolius L.）It also contains a certain amount of ginsenoside Re.

1. Extraction and Separation Methods：
   Obtaining ginsenosides Re from plant materials usually follows the following steps:
   • Preprocessing Crush the dried roots or rhizomes of ginseng or Panax notoginseng to increase the solvent contact area.
   • Extract Common solvent extraction methods include:
     • Alcohol extraction method Using methanol, ethanol, or ethanol aqueous solutions of different concentrations for reflux extraction or ultrasound assisted extraction. This method is highly efficient and is a commonly used method in laboratory and industrial production.
     • Water extraction method Traditional methods, but for saponin components, the alcohol extraction method usually yields higher yields.
   • Enrichment and Purification After vacuum concentration, the crude extract was separated and purified using the polarity of ginsenoside Re and its differences from other saponins.
     • Macroporous adsorption resin method Commonly used resins such as AB-8 and D101 are washed with water to remove impurities, and then eluted with different concentrations of ethanol gradient to effectively enrich ginsenoside Re.
     • Chromatography For obtaining high-purity monomers, it is necessary to use silica gel column chromatography, reverse phase silica gel column chromatography (such as ODS), high performance liquid chromatography (HPLC), or preparative liquid chromatography (pre HPLC) for fine separation. Acetonitrile water or methanol water systems are often used as mobile phases.
       In recent years, some green extraction techniques such as supercritical fluid extraction (SFE) and microwave-assisted extraction (MAE) have also been explored to improve extraction efficiency and reduce the use of organic solvents.

Pharmacological activity research

Numerous in vitro and in vivo studies have shown that ginsenoside Re has a wide range of pharmacological activities, with neuroprotective and anti-inflammatory effects being the most prominent.

1. Neuroprotective effect：
   This is the most concerned area of activity for ginsenoside Re. Research has confirmed that it exhibits clear protective effects in various AD cell and animal models.

   • Anti A β toxicity The abnormal aggregation and deposition of A β peptide is one of the core pathological features of AD. Ginsenoside Re can significantly reduce the level of A β in cells or brain tissue. The mechanism involves inhibiting the activity of key enzymes involved in A β production, such as BACE1, and potentially promoting the clearance of A β.
   • Reduce excessive phosphorylation of tau protein Abnormal phosphorylation of tau protein leading to neurofibrillary tangles is another major pathological feature of AD. Ginsenoside Re can inhibit the excessive phosphorylation of tau protein by regulating the activity of kinases such as GSK3 β.
   • anti-oxidative stress Ginsenoside Re can activate the cellular defense system, such as upregulating the expression of nuclear factor E2 related factor 2 (Nrf2) and its downstream antioxidant enzymes, thereby clearing reactive oxygen species (ROS) and reducing oxidative stress damage to neurons.
   • anti-apoptotic In a neural injury model, ginsenoside Re can upregulate the expression of anti apoptotic protein Bcl-2, inhibit the activity of pro apoptotic proteins such as Bax, and reduce the activation of apoptosis executing proteins such as caspase-9, thereby inhibiting neuronal apoptosis.
   • Improving synaptic plasticity and cognitive function In AD model animals, administration of ginsenoside Re can improve long-term potentiation (LTP) in the hippocampus and enhance learning and memory abilities, as demonstrated in water maze and dark avoidance experiments.

2. anti-inflammatory effect：
   Chronic neuroinflammation is an important driving factor for neurodegenerative diseases. Ginsenoside Re exerts anti-inflammatory effects through multiple targets.

   • Inhibition of NF - κ B pathway Nuclear factor kappa B (NF - κ B) is the core transcription factor in inflammatory response. Ginsenoside Re can inhibit the phosphorylation and degradation of I κ B α, prevent nuclear translocation of NF - κ B p65 subunit, and downregulate the gene expression of pro-inflammatory factors such as tumor necrosis factor - α (TNF - α), interleukin-1 β (IL-1 β), and interleukin-6 (IL-6).
   • Regulating the MAPK pathway Especially inhibiting the phosphorylation activation of c-Jun N-terminal kinase (JNK), blocking the downstream transmission of pro-inflammatory and pro apoptotic signals.

3. Other activities：

   • Cardiovascular protection Research has shown that it has potential effects such as vasodilation, improvement of myocardial ischemia, and anti arrhythmic effects.
   • Anti fatigue and immune enhancement Consistent with the traditional understanding of ginseng's "qi tonifying" effects.
   • Regulating blood sugar and metabolism It can improve diabetes and its complications.

Mechanism of action and molecular targets

The neuroprotective effect of ginsenoside Re is not achieved through a single target, but acts on a complex network, and its core mechanism and key molecular targets are as follows:

1. Regulating the A β metabolic pathway：

   • Targeting BACE1β - site amyloid precursor protein lyase 1 (BACE1) is a key rate limiting enzyme for the generation of A β. Ginsenoside Re can directly or indirectly inhibit the activity or expression of BACE1, reducing the production of A β.
   • Affects APP processing Perhaps by regulating the processing of amyloid precursor protein (APP), it can tilt towards non amyloid generation pathways.

2. Regulating the phosphorylation balance of tau protein：

   • Inhibit GSK3 βGlycogen synthase kinase-3 β (GSK3 β) is one of the most important phosphorylated kinases of tau protein. Ginsenoside Re can inhibit the activity of GSK3 β by activating upstream signals such as Akt, thereby reducing abnormal phosphorylation of tau protein.
   • Affects PP2A Possible promotion of tau protein dephosphorylation by regulating the activity of protein phosphatase 2A (PP2A).

3. Activate cellular self-protection pathways：

   • Activate Nrf2/ARE pathway Ginsenoside Re can promote the transfer of Nrf2 (encoded by NFE2L2 gene) from cytoplasm to nucleus, bind to antioxidant response elements (ARE), initiate the expression of phase II detoxifying enzymes and antioxidant proteins such as heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1), and enhance the cell's ability to resist oxidative damage.
   • Activate SIRT1 Silent Information Regulatory Factor 1 (SIRT1) is an NAD+- dependent deacetylase involved in energy metabolism, stress resistance, and aging regulation. Ginsenoside Re can upregulate the expression or activity of SIRT1, thereby deacetylating and activating downstream targets such as PGC-1 α and FOXO, improving mitochondrial function, and inhibiting oxidative stress and inflammation.

4. Inhibition of apoptotic signaling pathway：

   • Regulating Bcl-2 family proteins Upregulation of anti apoptotic protein Bcl-2 and possible downregulation of pro apoptotic protein Bax may stabilize mitochondrial membrane potential and prevent cytochrome c release.
   • Inhibit Caspase cascade reaction By the above pathway, the activation of caspase-9 is reduced, thereby inhibiting the activation of downstream caspase-3 and blocking the execution of apoptotic programs.

5. Regulating inflammation and stress signaling network：

   • Inhibition of NF - κ B and JNK pathways As mentioned earlier, by inhibiting the degradation of I κ B α and JNK phosphorylation, blocking the transcriptional activity of NF - κ B and AP-1, the neuroinflammatory response is suppressed from the source.
   • Regulating the MAPK/ERK pathway The extracellular signal regulated kinase (ERK, encoded by MAPK1) pathway is involved in cell survival and proliferation signaling. Ginsenoside Re may activate ERK and transmit survival promoting signals under certain conditions.

In summary, ginsenosides Re form a multidimensional and synergistic neuroprotective network by acting on multiple key targets such as APP/ACE1, GSK3 β/tau, Nrf2, SIRT1, Bcl-2/Aspase, NF - κ B/JNK, jointly combating the "multilevel" pathological process of AD, including A β toxicity, tau pathology, oxidative stress, inflammation, and apoptosis.

Evaluation of drug properties and pharmacokinetics

Although the pharmacological activity of ginsenoside Re is clear, its pharmacological properties, especially pharmacokinetic properties, are the main challenges facing its conversion into drugs.

1. absorb As a highly polar molecule, the oral bioavailability of ginsenoside Re is generally low. This is mainly attributed to:

   • Poor intestinal permeability High TPSA and molecular weight affect its passive transmembrane diffusion.
   • Metabolism of gut microbiota Ginsenoside Re is easily hydrolyzed by gut microbiota in the colon, removing some glycosides and converting them into secondary saponins (such as ginsenoside Rg1, Rh1, etc.) or aglycones. The activity and pharmacokinetic behavior of these metabolites are different from those of the original drug.
   • Function of external discharge pump Possible substrates of efflux transporters such as P-glycoprotein (P-gp) are actively pumped into the ileal lumen, reducing absorption.

2. distribution After entering the systemic circulation, ginsenoside Re can be distributed to multiple tissues, but its Low blood-brain barrier permeability It is a key bottleneck that restricts its direct central nervous system efficacy. Although studies have shown that it can be detected in the brain, the concentration is usually very low. The strategy includes developing prodrugs, using nanocarrier systems (such as liposomes, polymer nanoparticles), or combining with BBB penetration enhancers.

3. Metabolism In addition to gut microbiota metabolism, it may undergo Phase I (such as hydroxylation) and Phase II (such as glucuronidation and sulfation) metabolism in the liver. Its metabolites may be active and form a part of its overall pharmacological effect.

4. excretion Mainly excreted through the kidneys and bile.

5. Formulation strategy To improve its medicinal properties, current research focuses on:

   • Structural modification Synthesize lipophilic prodrugs or derivatives to enhance membrane permeability and BBB penetration ability.
   • New delivery system Develop nanocarriers based on lipids, polymers, or inorganic materials to encapsulate ginsenoside Re, in order to improve its solubility, stability, enhance targeting (such as brain targeting), and achieve sustained and controlled release.
   • combination therapy: Used in combination with other drugs or excipients that have synergistic effects and can improve their pharmacokinetic properties.

Clinical application prospects and prospects

Ginsenoside Re, as a natural compound with clear multi-target neuroprotective activity, has broad clinical application prospects, but further exploration is needed.

1. Potential application areas：

   • Alzheimer's disease and related cognitive impairment As a candidate drug or adjuvant therapy for disease modifying therapy (DMT), it intervenes in multiple pathological stages of AD. Especially suitable for interventions in early or mild cognitive impairment (MCI) stages to delay disease progression.
   • Other neurodegenerative diseases The anti-inflammatory, antioxidant, and anti apoptotic mechanisms of diseases such as Parkinson's disease (PD) and vascular dementia (VaD) are universal.
   • Cerebral ischemia/reperfusion injury Used as a neuroprotective agent in stroke treatment.
   • Neuroinflammatory related diseases Such as multiple sclerosis (MS), depression (related to neuroinflammation), etc.
   • cardiovascular disease As an adjuvant drug used for coronary heart disease, myocardial protection, etc.

2. challenges faced：

   • Pharmacokinetic bottleneck Low oral bioavailability and low BBB penetration are the primary challenges.
   • Complexity of mechanism of action Multi targeting is both an advantage and a challenge, requiring more precise elucidation of its main pathways and key targets in the human body to avoid potential off target effects.
   • Lack of clinical evidence At present, the vast majority of research is still in the preclinical stage (cell and animal experiments), lacking high-quality human clinical trial data to verify its effectiveness and safety.
   • Quality Control and Standardization As a natural product, its source, extraction process, and content in the formulation must be strictly standardized to ensure consistency between batches and reproducibility of therapeutic effects.

3. Future research directions：

   • In depth mechanism research Using techniques such as systems pharmacology, network pharmacology, proteomics, metabolomics, etc., comprehensively map its action network and identify the most core effector targets.
   • Innovative drug delivery Vigorously developing brain targeted delivery technologies, such as nanocarriers based on receptor-mediated transport (such as transferrin receptor and low-density lipoprotein receptor), is the key to promoting their clinical application.
   • Conduct clinical research After completing the non clinical safety evaluation (GLP toxicology) of the system, gradually advance Phase I (safety, pharmacokinetics) and Phase II (efficacy exploration) clinical trials.
   • Develop compound or combination therapies Exploring the combined use of ginsenosides Re with other neuroprotective drugs (such as donepezil, memantine, or other natural products) may result in synergistic effects, reducing their respective dosages and side effects.
   • Exploring biosynthesis Utilizing synthetic biology techniques to efficiently synthesize ginsenoside Re in microorganisms or plant cells, solving the problems of limited plant sources and high extraction costs.

Conclusion

Ginsenoside Re, as a natural active ingredient derived from traditional medicinal plants, has shown great potential in the field of neuroprotection due to its unique advantages of multi-target and multi pathway synergistic effects. It forms a comprehensive defense network against neurodegenerative diseases by regulating key pathological processes such as A β metabolism, tau protein phosphorylation, oxidative stress, neuroinflammation, and cell apoptosis. However, its inherent pharmacological defects, especially poor bioavailability and blood-brain barrier penetration ability, are the main obstacles that restrict its translation into clinical drugs. Future research should focus on improving its pharmacokinetic properties through strategies such as drug chemical modification and innovative drug delivery systems, while utilizing modern scientific technology to further elucidate its precise in vivo mechanism of action and actively promote standardized clinical evaluation. As these challenges are gradually overcome, ginsenoside Re is expected to evolve from a promising candidate molecule into an innovative drug for treating neurodegenerative diseases such as Alzheimer's disease, bringing new hope to the growing number of elderly patients with neurological disorders worldwide.