Scutellarin

• Neuroprotective
• Cardiovascular protection
• Anti-inflammatory
• Antioxidant

• Hepatoprotective
• Anticancer
• Antimicrobial
• Cognitive enhancement
• Cerebral circulation improvement

Scutellarin (scutellarein-7-O-glucuronide) exerts its diverse biological effects through multiple molecular pathways. As a prodrug, scutellarin itself has limited direct activity but is converted to its active form, scutellarein, by intestinal microflora β-glucuronidase enzymes. This metabolic activation is crucial for its bioactivity, and variations in gut microbiota composition can significantly affect its therapeutic efficacy. In the cardiovascular system, scutellarin demonstrates protective effects through several mechanisms.

It improves endothelial function by enhancing nitric oxide (NO) production through activation of endothelial nitric oxide synthase (eNOS) via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. This leads to vasodilation, improved blood flow, and reduced blood pressure. Scutellarin also inhibits platelet activation and aggregation by affecting calcium mobilization, thromboxane A2 production, and platelet glycoprotein IIb/IIIa expression, contributing to its antithrombotic effects. A particularly significant cardiovascular mechanism is scutellarin’s ability to improve microcirculation, especially cerebral microcirculation.

It reduces blood viscosity, inhibits erythrocyte aggregation, and improves erythrocyte deformability, enhancing blood flow through small vessels. This mechanism is especially relevant for its applications in ischemic stroke and vascular dementia. In the central nervous system, scutellarin exhibits neuroprotective effects through multiple mechanisms. It protects neurons from oxidative stress and excitotoxicity by reducing glutamate-induced calcium influx and maintaining mitochondrial function.

Scutellarin activates the PI3K/Akt/glycogen synthase kinase-3β (GSK-3β) pathway, which protects neurons from apoptosis and promotes cell survival. It also enhances the expression of brain-derived neurotrophic factor (BDNF) and activates the cAMP response element-binding protein (CREB), promoting neuronal survival, synaptic plasticity, and neurogenesis. In models of neurodegenerative diseases, scutellarin reduces amyloid-β aggregation and tau hyperphosphorylation, which may explain its potential benefits for Alzheimer’s disease. It also protects dopaminergic neurons through activation of the SIRT1 pathway and inhibition of neuroinflammation, potentially benefiting Parkinson’s disease.

As an anti-inflammatory agent, scutellarin inhibits the nuclear factor-kappa B (NF-κB) signaling pathway by preventing IκB kinase (IKK) activation and subsequent nuclear translocation of NF-κB, thereby reducing the expression of pro-inflammatory genes. It suppresses the production of inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), while inhibiting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression. Scutellarin also modulates the mitogen-activated protein kinase (MAPK) pathway, including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), further contributing to its anti-inflammatory properties. The antioxidant properties of scutellarin are mediated through both direct and indirect mechanisms.

After conversion to scutellarein, it can directly scavenge reactive oxygen species (ROS) and free radicals due to the hydroxyl groups in the scutellarein structure. Indirectly, scutellarin activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, leading to increased expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1). In cancer cells, scutellarin demonstrates multiple anticancer mechanisms. It induces apoptosis through both intrinsic (mitochondrial) and extrinsic (death receptor) pathways by modulating the expression of Bcl-2 family proteins, activating caspases, and promoting cytochrome c release.

Scutellarin inhibits cancer cell proliferation by arresting the cell cycle at G0/G1 or G2/M phases through regulation of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors such as p21 and p27. It also suppresses cancer cell migration and invasion by inhibiting matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT). Additionally, scutellarin has been shown to inhibit angiogenesis by reducing vascular endothelial growth factor (VEGF) expression and signaling. The glucuronide moiety in scutellarin contributes to its improved water solubility compared to its aglycone form (scutellarein), which may enhance its bioavailability in certain contexts.

However, this same feature limits its passive diffusion across cell membranes and the blood-brain barrier, necessitating its conversion to scutellarein or the use of enhanced delivery systems to maximize its therapeutic potential, particularly for neurological applications.

Dosage ranges for scutellarin vary depending on the form and indication. In clinical settings in China, breviscapine (an extract of Erigeron breviscapus standardized to contain >85% scutellarin) is commonly used at doses of 20-60 mg per day for cardiovascular and cerebrovascular conditions. For oral supplementation with standardized extracts, typical daily doses range from 50-200 mg of scutellarin or 300-1200 mg of standardized herbal extract containing 15-30% scutellarin.

For injectable forms (available in China as a pharmaceutical), typical doses are 20-30 mg per day administered intravenously.

Scutellarin has poor oral bioavailability, estimated at approximately 2-8% in animal studies.

This limited bioavailability is due to several factors: 1) As a glycoside with a glucuronic acid moiety, scutellarin has good water solubility but poor passive diffusion across cell membranes; 2)

It requires conversion to its aglycone form (scutellarein) by intestinal microflora β-glucuronidase enzymes for absorption, making its bioavailability highly dependent on gut microbiota composition; 3) Once converted to scutellarein and absorbed,

it undergoes extensive first-pass metabolism in the liver; 4)

It is subject to efflux by P-glycoprotein transporters in the intestine. The pharmacokinetics of scutellarin show significant inter-individual variability, largely due to differences in gut microbiota composition and activity. Injectable forms of scutellarin (as breviscapine) bypass

these absorption limitations and achieve much higher bioavailability, which explains their widespread use in clinical settings in China for acute conditions like ischemic stroke.

Nanoemulsion formulations – can increase bioavailability by 3-10 fold by improving solubility and enhancing intestinal permeability, Liposomal encapsulation – protects scutellarin from degradation and enhances cellular uptake, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, Phospholipid complexes – enhance lipid solubility and membrane permeability, Solid lipid nanoparticles – offer controlled release and improved stability, Combination with probiotics – may enhance conversion to scutellarein by modulating gut microbiota, Co-administration with piperine – inhibits P-glycoprotein efflux and intestinal metabolism, Cyclodextrin inclusion complexes – improve stability while maintaining water solubility, Micronization – reduces particle size to enhance dissolution rate, Injectable formulations – bypass intestinal absorption barriers entirely (available as pharmaceutical in some countries)

For oral scutellarin supplements, timing considerations are important due to its complex absorption process. Taking scutellarin on an empty stomach may enhance the activity of intestinal β-glucuronidase enzymes, potentially improving conversion to the absorbable scutellarein. However, some fat in the meal may enhance the absorption of the converted scutellarein. A practical approach is to take scutellarin 30 minutes before a light meal containing some fat.

For individuals with known or suspected gut dysbiosis, co-administration with probiotics may improve bioavailability by enhancing the conversion of scutellarin to scutellarein. Taking divided doses throughout the day may maintain more consistent blood levels due to scutellarin’s relatively short half-life (approximately 2-4 hours). For neuroprotective and cognitive effects, morning dosing may be beneficial, while for cardiovascular protection, consistent daily dosing is more important than specific timing. Enhanced delivery formulations like nanoemulsions or liposomes may have different optimal timing recommendations based on their specific pharmacokinetic profiles.

For injectable forms (where available), administration is typically performed in clinical settings according to established protocols, often once daily for a course of 14-28 days for conditions like acute ischemic stroke.

• Gastrointestinal discomfort (mild to moderate)
• Nausea (uncommon)
• Diarrhea (uncommon)
• Headache (rare)
• Dizziness (rare)
• Allergic reactions (rare)
• Facial flushing (primarily with injectable forms)
• Hypotension (primarily with injectable forms or high oral doses)
• Injection site reactions (with injectable forms)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Scheduled surgery (discontinue 2 weeks before due to potential anticoagulant effects)
• Bleeding disorders (due to antiplatelet activity)
• Severe hypotension (may further lower blood pressure)
• Individuals taking anticoagulant or antiplatelet medications (due to potential additive effects)
• Individuals with severe liver or kidney disease (due to limited data on metabolism and excretion in these populations)
• Known allergy to Asteraceae/Compositae family plants (for Erigeron breviscapus extracts)

• Anticoagulant and antiplatelet medications (may enhance bleeding risk due to scutellarin’s antiplatelet effects)
• Antihypertensive medications (may enhance blood pressure-lowering effects)
• Cytochrome P450 substrates (may affect metabolism of drugs metabolized by CYP1A2, CYP2C9, CYP2D6, and CYP3A4)
• P-glycoprotein substrates (may alter drug transport and absorption)
• Statins (potential for increased bioavailability and risk of side effects)
• Immunosuppressants (may interfere with therapeutic effects through immunomodulatory actions)
• Antidiabetic medications (may enhance blood glucose-lowering effects)
• Antibiotics that alter gut microbiota (may reduce conversion of scutellarin to scutellarein, potentially reducing efficacy)

Based on clinical studies with breviscapine in China, oral doses up to 200 mg of scutellarin daily appear to be well-tolerated in most individuals. For injectable forms, doses up to 30 mg daily have been used in clinical settings without significant adverse effects. For general supplementation, doses exceeding 200 mg of scutellarin or 1200 mg of standardized extract daily are not recommended without medical supervision due to potential drug interactions and limited long-term safety data at higher doses.

It ‘s important to note that most safety data comes from studies in China, and

there may be genetic or environmental factors that affect safety profiles in different populations.

Scutellarin is not approved as a drug by the FDA in the United States. Extracts containing scutellarin, such as Scutellaria baicalensis or Erigeron breviscapus extracts, are regulated as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) of 1994. Manufacturers cannot make specific disease treatment claims but may make general structure/function claims with appropriate disclaimers. The FDA has not evaluated the safety or efficacy of scutellarin specifically.

Injectable forms of breviscapine (the standardized extract containing >85% scutellarin) are not approved for use in the United States.

China: In China, scutellarin has the most advanced regulatory status. Breviscapine (the standardized extract of Erigeron breviscapus containing >85% scutellarin) is approved as a pharmaceutical drug by the National Medical Products Administration (NMPA, formerly CFDA). It is available in multiple formulations, including injectable solutions, tablets, and capsules. Breviscapine injection is included in the National Drug Reimbursement List and is widely used in hospitals for the treatment of ischemic stroke, coronary heart disease, and diabetic nephropathy. Erigeron breviscapus and Scutellaria baicalensis are also officially listed in the Chinese Pharmacopoeia as traditional Chinese medicines.

Eu: In the European Union, scutellarin is not approved as a medicinal product. Extracts containing scutellarin may be sold as food supplements, subject to the general food safety regulations. The European Food Safety Authority (EFSA) has not issued specific health claims for scutellarin or related extracts. Some EU member states may have their own regulations regarding traditional herbal medicinal products containing Scutellaria species, but Erigeron breviscapus is less commonly recognized in European regulatory frameworks.

Canada: Health Canada regulates Scutellaria baicalensis extracts containing scutellarin as Natural Health Products (NHPs). Several products have been issued Natural Product Numbers (NPNs), allowing them to be sold with specific health claims related to traditional use in Chinese medicine. Erigeron breviscapus extracts and isolated scutellarin are not specifically approved as standalone ingredients.

Australia: The Therapeutic Goods Administration (TGA) regulates Scutellaria baicalensis extracts as complementary medicines. Several products containing these extracts are listed on the Australian Register of Therapeutic Goods (ARTG). Traditional use claims are permitted with appropriate evidence of traditional use in Chinese medicine. Erigeron breviscapus extracts and scutellarin as an isolated compound are not specifically regulated.

Japan: Scutellaria baicalensis is included in the Japanese Pharmacopoeia and is a component of several Kampo medicine formulations approved by the Ministry of Health, Labour and Welfare for specific indications. Erigeron breviscapus extracts and scutellarin as an isolated compound are not specifically regulated for therapeutic use.

South Korea: Scutellaria baicalensis is recognized in the Korean Pharmacopoeia and is used in various traditional Korean medicine formulations. In recent years, there has been increasing research interest in scutellarin and breviscapine, but they are not specifically approved as pharmaceutical drugs.

Medium to high

Isolated scutellarin is available for research purposes at prices ranging from $100-$300 per gram, making

it relatively expensive but more affordable than many other isolated flavonoids. Standardized Erigeron breviscapus extracts (breviscapine) containing >85% scutellarin typically cost $1.50-$4.00 per day for oral formulations (tablets or capsules) and $5.00-$15.00 per day for injectable forms (where available, primarily in China). Standardized Scutellaria baicalensis extracts containing scutellarin along with other flavonoids typically cost $0.50-$2.00 per day for basic extracts and $2.00-$5.00 per day for premium, highly standardized formulations. Enhanced delivery formulations such as nanoemulsions or liposomes generally cost $3.00-$8.00 per day.

The cost-effectiveness of scutellarin varies significantly depending on the specific health condition and formulation used. For cerebrovascular conditions such as ischemic stroke recovery or vascular dementia, breviscapine (the standardized Erigeron breviscapus extract) offers good value despite its higher cost, as it has substantial clinical evidence supporting its efficacy for these specific conditions. The injectable form, while the most expensive, provides the highest bioavailability and has the strongest clinical evidence, making it potentially cost-effective for acute conditions when compared to conventional pharmaceutical treatments with similar indications. For oral supplementation, the poor bioavailability of standard formulations limits their cost-effectiveness, as much of the active compound is not absorbed.

Enhanced delivery systems such as nanoemulsions, liposomes, or SEDDS offer better value despite their higher cost due to significantly improved bioavailability (3-10 fold increase). For general neuroprotective, anti-inflammatory, and antioxidant benefits, Scutellaria baicalensis extracts may offer better value than pure scutellarin or breviscapine, as they contain multiple complementary flavonoids that work synergistically and are generally less expensive. When comparing the cost-effectiveness of scutellarin to other supplements with similar indications: For cerebrovascular conditions, scutellarin (as breviscapine) is comparable in cost to Ginkgo biloba and vinpocetine but may offer superior efficacy based on clinical evidence, particularly for post-stroke recovery. For general neuroprotection and cognitive support, scutellarin is more expensive than common options like Ginkgo biloba but may be justified for individuals with specific risk factors for cerebrovascular events.

For cardiovascular protection, scutellarin is generally more expensive than common options like CoQ10 or fish oil, but may offer unique benefits for microcirculation that justify the cost for certain individuals. The cost-effectiveness is also influenced by individual factors such as gut microbiota composition (which affects conversion of scutellarin to its active form) and specific health conditions, making personalized approaches important for maximizing value.

Pure scutellarin is moderately stable, with a typical shelf life of 2-3 years when properly stored. The glucuronic acid moiety provides better stability compared to its aglycone form (scutellarein). Standardized herbal extracts containing scutellarin typically have a shelf life of 1-2 years from the date of manufacture. Breviscapine injection (pharmaceutical form available in China) typically has a shelf life of 2 years when stored properly.

Enhanced delivery formulations such as nanoemulsions or liposomes generally have shorter shelf lives of 1-2 years, depending on the specific formulation and preservative system.

Store in a cool, dry place away from direct sunlight in airtight, opaque containers. Refrigeration is recommended for liquid formulations and can extend shelf life of extracts containing scutellarin. Protect from moisture, heat, oxygen, and light exposure, which can accelerate degradation. For research-grade pure scutellarin, storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability.

Injectable forms require specific storage conditions according to pharmaceutical guidelines, typically 2-8°C and protection from light. The addition of antioxidants such as vitamin E or ascorbic acid to formulations can help prevent oxidation and extend shelf life. Enhanced delivery formulations may have specific storage requirements provided by the manufacturer, which should be followed carefully to maintain stability and potency. Avoid repeated freeze-thaw cycles, particularly for liquid formulations, as this can destabilize the product.

Exposure to UV light and sunlight – causes photodegradation, though the glucuronic acid moiety provides some protection compared to the aglycone, High temperatures (above 30°C) – accelerates decomposition, Moisture – can promote hydrolysis of the glucuronic acid moiety and microbial growth, particularly in liquid formulations, Oxygen exposure – leads to oxidation, particularly of the hydroxyl groups in the flavone structure, pH extremes – scutellarin is most stable at slightly acidic to neutral pH (5-7), Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Enzymatic activity – β-glucuronidase enzymes can cleave the glucuronic acid moiety, converting scutellarin to scutellarein, Incompatible excipients in formulations – certain preservatives or other ingredients may interact negatively with scutellarin, Repeated freeze-thaw cycles – can destabilize enhanced delivery formulations such as nanoemulsions or liposomes

Synthesis Methods

Natural Sources

Quality Considerations

Scutellarin itself was not identified or isolated until the modern era, but it is a constituent of several plants that have been used in traditional medicine systems for centuries. While the specific contribution of scutellarin to the traditional uses of these plants was unknown to ancient practitioners, it is now recognized as one of the key bioactive compounds in these historically important medicinal materials. Scutellarin is primarily found in two main traditional medicinal sources: Erigeron breviscapus and Scutellaria species. Erigeron breviscapus, known as ‘Dengzhanxixin’ in Chinese medicine, has been used in traditional Chinese and folk medicine in the Yunnan province of China for centuries.

The name ‘Dengzhanxixin’ translates to ‘herba erigerontis’ or ‘herba erigerontis breviscapi.’ It was traditionally used by the Yi ethnic minority in Yunnan to treat paralysis, rheumatism, gastritis, and cardiovascular diseases. The whole plant, including flowers, leaves, and stems, was typically dried and prepared as a decoction or powder. Its use became more widespread in Chinese medicine during the mid-20th century, particularly for the treatment of cerebrovascular diseases. In Traditional Chinese Medicine (TCM), Erigeron breviscapus was classified as an herb that activates blood circulation, dispels wind, and clears heat.

It was traditionally used to treat conditions that would now be recognized as stroke, hypertension, coronary heart disease, and various inflammatory conditions. In Scutellaria baicalensis (Huang Qin or Chinese skullcap), which has been used in TCM for over 2,000 years, scutellarin is present alongside other flavonoids like baicalin, baicalein, and wogonin. The root was traditionally used to treat fevers, inflammation, respiratory infections, diarrhea, jaundice, and bleeding disorders. The first documented medicinal use of Scutellaria baicalensis appears in the ancient Chinese pharmacopeia ‘Shennong Bencao Jing’ (Divine Farmer’s Materia Medica), compiled around 200-250 CE.

The modern scientific interest in scutellarin began in the 1970s when researchers in China started investigating the active components of Erigeron breviscapus. Scutellarin was identified as one of the primary bioactive compounds, and its structure was elucidated as scutellarein-7-O-glucuronide. In the 1980s, a standardized extract of Erigeron breviscapus called ‘breviscapine’ was developed in China, standardized to contain at least 85% scutellarin. This extract was initially formulated as an injectable preparation for the treatment of cerebrovascular diseases, particularly ischemic stroke.

The development of breviscapine marked a significant transition from traditional herbal use to a more standardized, pharmaceutical approach. Since the 1990s, breviscapine has been widely used in Chinese hospitals for the treatment of various cerebrovascular and cardiovascular conditions, with numerous clinical trials supporting its efficacy and safety. In recent years, research on scutellarin has expanded globally, with studies investigating its potential applications in neurodegenerative diseases, cancer, and various inflammatory conditions. The development of enhanced delivery systems to overcome scutellarin’s poor oral bioavailability has been a focus of recent research, aiming to make this traditionally-derived compound more effective for modern therapeutic applications.