Astragaloside IV

• Neuroprotection
• Cardiovascular protection
• Anti-inflammatory effects
• Antioxidant activity

• Kidney protection
• Liver protection
• Immune modulation
• Blood glucose regulation
• Anti-fibrotic effects
• Wound healing promotion
• Telomerase activation (via metabolite cycloastragenol)

Astragaloside IV (AS-IV) exerts its diverse biological effects through multiple molecular mechanisms and signaling pathways. As a potent antioxidant, AS-IV enhances cellular defense systems by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which upregulates antioxidant enzymes including superoxide dismutase (SOD), catalase, glutathione peroxidase, and heme oxygenase-1 (HO-1). This activation significantly reduces oxidative stress and protects cells from reactive oxygen species (ROS)-induced damage. AS-IV exhibits strong anti-inflammatory properties by inhibiting the nuclear factor-kappa B (NF-κB) signaling pathway, a master regulator of inflammation.

This inhibition reduces the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Additionally, AS-IV suppresses the activation of the NLRP3 inflammasome, further contributing to its anti-inflammatory effects. In the cardiovascular system, AS-IV protects against myocardial ischemia-reperfusion injury through multiple mechanisms, including activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, which promotes cell survival and prevents apoptosis. It also enhances the expression and activity of sarco/endoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a), improving calcium handling in cardiomyocytes.

AS-IV promotes angiogenesis by increasing vascular endothelial growth factor (VEGF) expression and activating the hypoxia-inducible factor-1 alpha (HIF-1α) pathway. For neuroprotection, AS-IV crosses the blood-brain barrier, albeit in limited amounts, and protects neurons from excitotoxicity, oxidative stress, and inflammation. It modulates neurotransmitter systems, particularly dopaminergic and cholinergic pathways, and promotes neurogenesis by enhancing brain-derived neurotrophic factor (BDNF) expression. AS-IV also inhibits neuroinflammation by suppressing microglial activation and reducing pro-inflammatory cytokine production in the central nervous system.

In metabolic regulation, AS-IV improves insulin sensitivity by activating the AMP-activated protein kinase (AMPK) pathway and enhancing glucose transporter type 4 (GLUT4) translocation to the cell membrane. It also protects pancreatic β-cells from oxidative damage and promotes their survival and function. For kidney protection, AS-IV inhibits the transforming growth factor-beta 1 (TGF-β1)/Smad signaling pathway, reducing renal fibrosis and epithelial-to-mesenchymal transition (EMT). It also activates autophagy through AMPK signaling, which helps clear damaged cellular components and protects against kidney injury.

AS-IV’s immunomodulatory effects include enhancing T-cell function, promoting macrophage phagocytosis, and regulating the balance between T helper 1 (Th1) and T helper 2 (Th2) responses. It also increases natural killer (NK) cell activity and modulates B-cell function. At the epigenetic level, AS-IV can influence DNA methylation patterns and histone modifications, potentially affecting gene expression related to aging and disease processes. Its metabolite, cycloastragenol, has been shown to activate telomerase, which may contribute to cellular longevity.

The molecular structure of AS-IV, with its multiple hydroxyl groups and glycosidic bonds, allows it to interact with various cellular receptors and enzymes, contributing to its pleiotropic effects. However, its large molecular size and hydrophilic nature limit its bioavailability and cellular penetration, which may affect its in vivo efficacy.

The optimal dosage of Astragaloside IV is not well-established in humans due to limited clinical trials

specifically using purified Astragaloside IV. Most research has been conducted using Astragalus extracts containing variable amounts of Astragaloside IV. Based on preclinical studies and limited human research, dosages typically range from 5-20 mg of purified Astragaloside IV daily.

When using Astragalus extracts standardized for Astragaloside IV content, products typically contain 0.1-0.5% Astragaloside IV, with recommended dosages of the extract ranging from 500-3000 mg daily.

Astragaloside IV (AS-IV) exhibits poor oral bioavailability, typically less than 3% in animal studies. This low bioavailability is primarily attributed to its large molecular size (molecular weight of 784.97 g/mol), poor water solubility, limited lipid solubility, and extensive first-pass metabolism in the liver. AS-IV is a substrate for P-glycoprotein efflux transporters in the intestinal epithelium, which actively pump the compound back into the intestinal lumen, further limiting its absorption. Additionally, AS-IV undergoes significant hydrolysis in the gastrointestinal tract by intestinal bacteria and digestive enzymes, converting it to its aglycone form, cycloastragenol, which may have different bioactivity profiles.

After absorption, AS-IV distributes primarily to highly perfused organs including the liver, kidneys, and lungs, with limited penetration across the blood-brain barrier (estimated at less than 0.1% of plasma concentrations). The plasma half-life of AS-IV in humans is estimated to be approximately 4-6 hours based on limited pharmacokinetic studies.

Liposomal encapsulation: Incorporating AS-IV into liposomes has been shown to increase bioavailability by 2-3 fold in animal studies by enhancing intestinal absorption and reducing P-glycoprotein efflux, Nanoparticle formulations: Polymeric nanoparticles and solid lipid nanoparticles can improve AS-IV solubility and protect it from degradation in the gastrointestinal tract, potentially increasing bioavailability by 3-5 fold, Phospholipid complexes: Forming complexes with phospholipids (phytosomes) increases the lipophilicity of AS-IV, enhancing its ability to cross cell membranes and improving bioavailability by 2-4 fold, Self-microemulsifying drug delivery systems (SMEDDS): These formulations can increase AS-IV solubility and provide a large surface area for absorption, potentially improving bioavailability by 4-6 fold, Co-administration with P-glycoprotein inhibitors: Natural compounds like piperine or quercetin may inhibit P-glycoprotein efflux and enhance AS-IV absorption, Micronization: Reducing particle size increases the surface area available for dissolution and absorption, Cyclodextrin inclusion complexes: These can improve AS-IV solubility and stability in the gastrointestinal environment, Enteric coating: Protects AS-IV from degradation in the stomach and targets release in the intestines where absorption is more favorable, Co-administration with absorption enhancers: Compounds like sodium caprate or chitosan derivatives may increase paracellular transport of AS-IV across the intestinal epithelium

Due to its poor bioavailability and interaction with food components, the timing of Astragaloside IV administration can significantly impact its absorption and efficacy. Taking AS-IV on an empty stomach (at least 30 minutes before meals or 2 hours after meals) may enhance absorption by minimizing interference from food components and digestive processes. However, some individuals may experience mild gastrointestinal discomfort when taking AS-IV on an empty stomach, in which case taking it with a small amount of fat (such as a teaspoon of olive oil or coconut oil) may improve tolerability while potentially enhancing absorption through increased bile secretion and lymphatic transport. For cardiovascular and metabolic benefits, consistent daily dosing is recommended, with some evidence suggesting that dividing the daily dose into two administrations (morning and evening) may provide more stable plasma levels.

For immune modulation, some traditional practices suggest cyclical use (e.g., 3 weeks on, 1 week off) rather than continuous administration, though scientific evidence for this approach is limited. When using AS-IV for neuroprotection, morning administration may be preferable to align with natural circadian rhythms of neuroprotective mechanisms, though this recommendation is based on theoretical considerations rather than direct evidence. Consistency in daily administration is generally more important than specific timing for achieving long-term benefits with AS-IV supplementation.

• Mild gastrointestinal discomfort (nausea, bloating, diarrhea)
• Headache (uncommon)
• Dizziness (rare)
• Skin rash or itching (rare, may indicate allergic reaction)
• Fatigue (uncommon)
• Dry mouth (uncommon)
• Hypotension (rare, more common with high doses)
• Increased urination (due to mild diuretic effect)
• Mild immunostimulatory effects (potentially problematic in autoimmune conditions)

• Known allergy or hypersensitivity to Astragalus or related plants in the Fabaceae family
• Autoimmune diseases (including multiple sclerosis, lupus, rheumatoid arthritis) due to potential immune-stimulating effects
• Pregnancy and breastfeeding (due to insufficient safety data)
• Scheduled surgery (discontinue at least 2 weeks before due to potential effects on blood clotting and blood pressure)
• Severe liver or kidney disease (due to limited data on metabolism and elimination in these conditions)
• Organ transplant recipients taking immunosuppressive medications
• Individuals with hormone-sensitive conditions such as breast cancer, uterine cancer, ovarian cancer, endometriosis, or uterine fibroids (theoretical concern due to potential phytoestrogenic effects)

• Immunosuppressant medications (may counteract therapeutic effects due to immunostimulatory properties)
• Antihypertensive medications (may enhance blood pressure-lowering effects)
• Anticoagulant and antiplatelet medications (may have additive effects on blood clotting)
• Hypoglycemic medications (may enhance blood glucose-lowering effects)
• Diuretics (may have additive effects on urine output)
• Cytochrome P450 substrates (potential for interactions, though specific effects on CYP enzymes are not well-characterized)
• Medications metabolized by P-glycoprotein (AS-IV may compete for the same transport mechanisms)
• Hormone replacement therapy or hormonal contraceptives (theoretical interaction due to potential phytoestrogenic effects)

No established upper limit has been determined for Astragaloside IV in humans. In animal studies, doses up to 100 mg/kg body weight have been used without significant acute toxicity, though such high doses are not relevant for human supplementation. Based on available research and traditional use of Astragalus, a conservative upper limit for purified Astragaloside IV would be approximately 40 mg daily for adults. For Astragalus extracts standardized to contain 0.3-0.5% Astragaloside IV, an upper limit of 6000 mg of extract daily would be reasonable.

However, these are theoretical limits based on limited data, and individual sensitivity may vary. As with any supplement, it is advisable to start with lower doses and gradually increase as tolerated, particularly for individuals with sensitive systems or pre-existing health conditions.

In the United States, purified Astragaloside IV is not approved as a drug by the FDA for any specific indication. It may be sold as a dietary supplement ingredient under the Dietary Supplement Health and Education Act (DSHEA) of 1994, provided it meets the definition of a dietary ingredient and was not first marketed as a drug. As a supplement ingredient, Astragaloside IV or Astragalus extracts standardized for Astragaloside IV content cannot make claims to diagnose, treat, cure, or prevent any disease. Structure/function claims (e.g., ‘supports cardiovascular health’) are permitted with appropriate disclaimer statements.

The FDA has not established a specific regulatory framework or monograph for Astragaloside IV. Astragalus root, the natural source of Astragaloside IV, is generally recognized as safe (GRAS) for use in dietary supplements and has a long history of use in traditional medicine.

Eu: In the European Union, purified Astragaloside IV is not approved as a medicinal product by the European Medicines Agency (EMA). Astragalus membranaceus root, which contains Astragaloside IV, is recognized in the European Pharmacopoeia and may be used in traditional herbal medicinal products or food supplements. The European Food Safety Authority (EFSA) has not approved any health claims for Astragaloside IV or Astragalus extracts. As a novel food ingredient, highly concentrated Astragaloside IV extracts may require novel food authorization under Regulation (EU) 2015/2283 if they do not have a significant history of consumption in the EU before May 1997.

Canada: Health Canada has not approved Astragaloside IV as a prescription drug. Astragalus membranaceus root is listed in the Natural Health Products Ingredients Database with traditional uses related to immune function and as an adaptogen. Products containing Astragalus extracts standardized for Astragaloside IV content may be sold as Natural Health Products (NHPs) with appropriate licenses, though specific claims are limited and must be supported by evidence. Health Canada has not established specific monographs or regulatory frameworks specifically for purified Astragaloside IV.

Australia: The Therapeutic Goods Administration (TGA) has not approved Astragaloside IV as a prescription medicine in Australia. Astragalus membranaceus is recognized in the TGA’s list of permitted ingredients for listed medicines (ARTG ID: 10218). Products containing Astragalus extracts standardized for Astragaloside IV content may be sold as listed complementary medicines, subject to quality and safety requirements. Specific therapeutic claims require higher levels of evidence and appropriate registration.

China: In China, Astragaloside IV has the most advanced regulatory status. Astragalus membranaceus (Huangqi) is officially listed in the Chinese Pharmacopoeia, with Astragaloside IV serving as one of the quality control markers. Several pharmaceutical preparations containing Astragalus extracts standardized for Astragaloside IV content are approved as traditional Chinese medicines for various indications, particularly for cardiovascular and immune support. Purified Astragaloside IV is used in some approved pharmaceutical preparations and is the subject of ongoing clinical research for specific indications, particularly for diabetic nephropathy and cardiovascular conditions.

Japan: In Japan, Astragaloside IV is not approved as a pharmaceutical drug. Astragalus root (Ogi in Japanese) is recognized in the Japanese Pharmacopoeia and is used in some Kampo (traditional Japanese herbal medicine) formulations. Products containing Astragalus extracts may be sold as Foods with Health Claims under appropriate categories if they meet the established requirements, though specific approved claims for Astragaloside IV have not been established.

Purified Astragaloside IV is among the more expensive natural compounds available as supplements, with a relative cost rating of high to very high.

This high cost is primarily due to the complex extraction and purification processes required, the relatively low concentration in the raw material (typically 0.1-0.5% in Astragalus root), and the growing demand for pharmaceutical-grade material for research and development. Standardized Astragalus extracts with specified Astragaloside IV content (typically 0.3-0.5%) have a medium to high relative cost, significantly lower than purified Astragaloside IV but higher than many common herbal supplements. Whole Astragalus root powder or basic Astragalus extracts (not standardized for Astragaloside IV) have a low to medium relative cost and represent the most economical way to obtain some Astragaloside IV, albeit in variable and typically lower amounts.

For purified Astragaloside IV (≥98% purity), the cost per effective daily dose (10-20 mg) typically ranges from $5-15, making

it prohibitively expensive for most consumers for long-term use. For standardized Astragalus extracts (0.3-0.5% Astragaloside IV), the cost per effective daily dose (providing approximately 5-15 mg of Astragaloside IV from 1000-3000 mg of extract) ranges from $1-4, representing a more accessible option though still relatively expensive compared to many supplements. For whole Astragalus root powder or basic extracts, the cost per daily dose (typically 3-9 grams of root powder or 1-3 grams of basic extract) ranges from $0.30-1.50, though the Astragaloside IV content is variable and often lower than the theoretically effective dose based on research studies. Novel delivery systems designed to enhance bioavailability, such as liposomal or nanoparticle formulations, typically command premium prices of $5-20 per daily dose, though

they may potentially deliver more bioavailable Astragaloside IV.

The value proposition of Astragaloside IV varies significantly depending on the form, intended use, and individual health considerations. Purified Astragaloside IV, despite its high cost, may offer value for specific research applications or short-term therapeutic interventions where precise dosing is critical. However, for most consumers seeking general health benefits, the cost-to-benefit ratio does not currently justify the expense of purified Astragaloside IV supplements, particularly given the limited human clinical evidence and bioavailability challenges. Standardized Astragalus extracts with verified Astragaloside IV content offer a more reasonable value proposition, providing a balance between cost and potential efficacy.

These products benefit from the potential synergistic effects of other compounds naturally present in Astragalus, which may enhance overall efficacy beyond what would be expected from Astragaloside IV alone. Whole Astragalus root or basic extracts provide the best value for general health maintenance and traditional uses, supported by centuries of traditional use and a growing body of scientific evidence for the whole herb. While the Astragaloside IV content is lower and less standardized, the presence of multiple bioactive compounds may provide complementary benefits. For specific health conditions with stronger research support, such as cardiovascular protection or kidney support, the value proposition of standardized extracts improves, as the potential health benefits may offset the moderate cost.

However, even in these cases, the limited bioavailability of Astragaloside IV remains a significant factor limiting overall value. Future developments in delivery systems to enhance bioavailability may significantly improve the value proposition of Astragaloside IV supplements, potentially justifying higher costs if they can demonstrate proportionally increased bioavailability and efficacy in human studies.

Purified Astragaloside IV in powder form,

when properly stored, typically has a shelf life of 2-3 years. In standardized Astragalus extracts, the shelf life is generally 1-2 years, depending on the specific formulation and storage conditions. Liquid formulations containing Astragaloside IV tend to have shorter shelf lives of approximately 1 year due to increased potential for hydrolysis and microbial growth. Novel formulations such as liposomal or nanoparticle preparations may have different stability profiles and should be evaluated on a case-by-case basis.

Purified Astragaloside IV powder should be stored in airtight containers protected from light, heat, and moisture. Optimal storage temperature is between 2-8°C (refrigerated), though room temperature storage (15-25°C) is acceptable for short periods. Desiccants should be used in the container to minimize moisture exposure. For standardized Astragalus extracts containing Astragaloside IV, storage in tightly sealed, opaque containers at room temperature (15-25°C) away from direct sunlight is generally sufficient.

Liquid formulations may require refrigeration after opening to prevent microbial growth. Freeze-thaw cycles should be avoided for all formulations as they can accelerate degradation. For long-term storage of research-grade material, storage at -20°C under inert gas (nitrogen or argon) is recommended.

Hydrolysis: Astragaloside IV is susceptible to hydrolysis, particularly in acidic or alkaline conditions, which can cleave the glycosidic bonds and convert it to cycloastragenol or other metabolites, Oxidation: Exposure to oxygen, especially in combination with light or heat, can lead to oxidative degradation of the molecule, Heat: Temperatures above 40°C significantly accelerate degradation through multiple mechanisms, Light: Direct sunlight or UV light exposure promotes photodegradation, Moisture: High humidity environments accelerate hydrolysis and may promote microbial growth in formulations, Microbial contamination: Certain microorganisms can enzymatically degrade Astragaloside IV, Enzymatic degradation: Beta-glucosidases and similar enzymes can cleave the glycosidic bonds, pH extremes: Both strongly acidic (pH < 3) and alkaline (pH > 9) conditions accelerate degradation, Metal ions: Certain metal ions, particularly iron and copper, can catalyze oxidative degradation, Incompatible excipients: Some pharmaceutical excipients may interact with Astragaloside IV and reduce stability

Synthesis Methods

Natural Sources

Quality Considerations

While Astragaloside IV itself was not specifically identified or isolated until modern times, its primary source, Astragalus membranaceus (Huangqi), has a rich history spanning over 2,000 years in traditional Chinese medicine (TCM). Astragalus root was first documented in the Shennong Ben Cao Jing (Divine Farmer’s Materia Medica), one of the earliest Chinese pharmacopeias compiled around 200 CE. In this ancient text, Astragalus was classified as a ‘superior herb,’ the highest category reserved for herbs that were believed to promote longevity, strengthen vital energy (Qi), and harmonize body functions without toxicity. Traditionally, Astragalus was primarily used to ‘tonify Qi’ (strengthen vital energy), ‘lift Yang’ (counteract collapse), strengthen the exterior (immune defense), promote tissue regeneration, and reduce swelling.

It was particularly valued for treating conditions characterized by Qi deficiency, including fatigue, weakness, frequent colds, spontaneous sweating, and chronic illnesses. In TCM formulations, Astragalus was often combined with other herbs in complex prescriptions tailored to specific conditions. Common traditional combinations included Astragalus with Angelica sinensis (Dong Quai) for blood deficiency, with Glycyrrhiza uralensis (Licorice) for digestive weakness, and with Atractylodes macrocephala for spleen Qi deficiency. The herb was typically prepared as a decoction (tea), powder, or incorporated into honey pills.

In some cases, it was also applied externally for wounds and abscesses. Beyond China, Astragalus species were used in traditional medicine systems across Asia, including in Korean, Japanese, and Mongolian medicine, though specific applications varied by region and cultural context. In modern times, scientific research began to focus on identifying the active compounds in Astragalus, leading to the isolation and characterization of Astragaloside IV in the late 20th century. This research revealed that Astragaloside IV is one of the primary bioactive compounds responsible for many of the traditional uses of Astragalus, particularly its immune-modulating, cardiovascular, and adaptogenic effects.

The identification of Astragaloside IV has allowed for more targeted research into specific therapeutic applications and has facilitated the development of standardized extracts and purified compounds for both research and commercial purposes. Today, while whole Astragalus root and its extracts remain widely used in traditional and integrative medicine practices, purified Astragaloside IV represents a bridge between traditional herbal medicine and modern pharmacological approaches, embodying the ongoing evolution of traditional knowledge through scientific investigation.

No formal meta-analyses specifically focused on Astragaloside IV have been published to date. Most meta-analyses have examined Astragalus preparations in general, which contain variable amounts of Astragaloside IV along with other bioactive compounds.

Limited information is available on ongoing clinical trials specifically using purified Astragaloside IV. Most current clinical research involves Astragalus extracts or traditional Chinese medicine formulations containing Astragalus, where Astragaloside IV is one of many bioactive components., Several preclinical studies are investigating novel delivery systems to improve the bioavailability of Astragaloside IV, including nanoparticle formulations, liposomal encapsulation, and structural modifications., Research is ongoing to better understand the pharmacokinetics and metabolism of Astragaloside IV in humans, which will be crucial for optimizing dosing strategies in future clinical applications.