Scutellarein

• Neuroprotective
• Anti-inflammatory
• Antioxidant
• Anticancer

• Cardiovascular protection
• Hepatoprotective
• Antimicrobial
• Anxiolytic
• Cognitive enhancement

Scutellarein (5,6,7,4′-tetrahydroxyflavone) exerts its diverse biological effects through multiple molecular pathways. As a flavone with four hydroxyl groups, scutellarein possesses potent antioxidant properties through both direct and indirect mechanisms. Directly, it scavenges reactive oxygen species (ROS) and free radicals due to its hydroxyl groups, which can donate hydrogen atoms to neutralize these harmful molecules. The presence of a catechol structure in the B-ring (3′,4′-dihydroxy) and the 5,7-dihydroxy arrangement in the A-ring contribute significantly to its radical scavenging capacity.

Indirectly, scutellarein 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). As an anti-inflammatory agent, scutellarein 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. Scutellarein 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.

In the central nervous system, scutellarein exhibits neuroprotective effects through multiple mechanisms. It protects neurons from oxidative stress and excitotoxicity by reducing glutamate-induced calcium influx and maintaining mitochondrial function. Scutellarein activates the phosphatidylinositol 3-kinase (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, scutellarein 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. In cancer cells, scutellarein 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.

Scutellarein 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, scutellarein has been shown to inhibit angiogenesis by reducing vascular endothelial growth factor (VEGF) expression and signaling. In the cardiovascular system, scutellarein demonstrates protective effects by improving endothelial function, reducing platelet aggregation, and modulating lipid metabolism.

It enhances nitric oxide (NO) production by activating endothelial nitric oxide synthase (eNOS), promoting vasodilation and improving blood flow. Scutellarein also inhibits platelet activation and aggregation by affecting calcium mobilization and thromboxane A2 production. Furthermore, it improves lipid profiles by enhancing reverse cholesterol transport and inhibiting cholesterol synthesis through modulation of key enzymes like HMG-CoA reductase. Scutellarein’s anxiolytic effects are mediated through modulation of the gamma-aminobutyric acid (GABA) system, potentially by acting as a positive allosteric modulator of GABA-A receptors.

This mechanism contributes to its calming and anxiolytic properties without significant sedation. The tetrahydroxy structure of scutellarein contributes to its moderate water solubility compared to more methoxylated flavones, which may enhance its bioavailability. However, it is still subject to extensive metabolism, primarily through glucuronidation and sulfation, which can limit its bioavailability and necessitate various formulation strategies to enhance its absorption and therapeutic potential. It’s important to note that scutellarein is often confused with scutellarin, which is actually the 7-O-glucuronide of scutellarein.

Scutellarin is more commonly found in herbal extracts and has been more extensively studied, while scutellarein is the aglycone form that may be produced in the body after metabolism of scutellarin.

Optimal dosage ranges for scutellarein in humans have not been well established through clinical trials. Most studies use Scutellaria baicalensis or Erigeron breviscapus extracts standardized to contain specific percentages of flavonoids, including scutellarein or its glycoside form scutellarin.

It ‘s important to note that scutellarein itself is rarely available as an isolated supplement, and most commercial products contain scutellarin (the 7-O-glucuronide of scutellarein) or a mixture of flavonoids from herbal extracts. Based on preclinical studies and limited human research with related compounds, typical daily doses range from 30-150 mg of scutellarein or 300-900 mg of standardized herbal extract containing 5-15% flavonoids.

Scutellarein has moderate oral bioavailability, estimated at approximately 5-15% in animal studies. This is higher than many highly methoxylated flavones due to its tetrahydroxy structure, which provides better water solubility. However, its bioavailability is still limited by several factors, including first-pass metabolism in the liver, efflux by P-glycoprotein transporters in the intestine, and extensive phase II metabolism (primarily glucuronidation and sulfation). It’s important to note that scutellarein is often found in plants as its glycoside form, scutellarin (scutellarein-7-O-glucuronide).

After oral administration, scutellarin is poorly absorbed directly and must be hydrolyzed by intestinal microflora to release scutellarein, which is then absorbed and subsequently undergoes extensive metabolism. This complex absorption and metabolism pathway contributes to the variable bioavailability observed in different individuals, which may be influenced by gut microbiota composition.

Nanoemulsion formulations – can increase bioavailability by 3-10 fold by improving solubility and enhancing intestinal permeability, Liposomal encapsulation – protects scutellarein from degradation and enhances cellular uptake, Self-emulsifying drug delivery systems (SEDDS) – improve dissolution and absorption in the gastrointestinal tract, Phospholipid complexation – enhances lipid solubility and membrane permeability, Microemulsions – provide a stable delivery system with enhanced solubility, Combination with piperine – inhibits P-glycoprotein efflux and intestinal metabolism, Co-administration with probiotics – may enhance hydrolysis of scutellarin to scutellarein by modulating gut microbiota, Cyclodextrin inclusion complexes – improve aqueous solubility while maintaining stability, Solid dispersion techniques – enhance dissolution rate and solubility, Co-administration with other flavonoids that may compete for metabolic enzymes, potentially extending scutellarein’s half-life

Scutellarein is best absorbed when taken with meals containing some fat, which can enhance solubility and stimulate bile secretion, improving dissolution and absorption. The presence of other flavonoids may enhance scutellarein’s bioavailability through competitive inhibition of metabolic enzymes or transporters. For neuroprotective and cognitive effects, consistent daily dosing is important, with some evidence suggesting that morning dosing may be beneficial for cognitive enhancement during the day. For anxiolytic or sleep benefits, taking a dose in the evening may be beneficial due to its potential GABA-modulating effects.

Taking divided doses throughout the day may maintain more consistent blood levels due to scutellarein’s relatively short half-life (approximately 2-4 hours in animal studies). Enhanced formulations like nanoemulsions or liposomes may have different optimal timing recommendations based on their specific pharmacokinetic profiles, but generally follow the same principles of taking with food for optimal absorption. For individuals taking scutellarin (the glycoside form), allowing sufficient time for intestinal microflora to hydrolyze it to scutellarein is important, which suggests taking it at least 30-60 minutes before meals may be beneficial for some individuals, though this may vary based on individual gut microbiota composition.

• Gastrointestinal discomfort (mild to moderate)
• Nausea (uncommon)
• Diarrhea (uncommon)
• Headache (rare)
• Dizziness (rare)
• Allergic reactions (rare)
• Mild drowsiness or sedation (due to potential GABA-modulating effects)
• Dry mouth (uncommon)

• Pregnancy and breastfeeding (due to insufficient safety data)
• Scheduled surgery (discontinue 2 weeks before due to potential anticoagulant effects)
• Bleeding disorders (due to potential antiplatelet activity)
• Hormone-sensitive conditions (due to potential phytoestrogenic effects)
• Individuals taking medications metabolized by CYP450 enzymes (due to potential interactions)
• Individuals with severe liver or kidney disease (due to limited data on metabolism and excretion in these populations)

• Anticoagulant and antiplatelet medications (may enhance bleeding risk due to potential antiplatelet effects)
• Sedatives and CNS depressants (may enhance sedative effects through potential GABA-modulating activity)
• Cytochrome P450 substrates (may affect metabolism of drugs metabolized by CYP1A2, CYP2C9, CYP2D6, and CYP3A4)
• P-glycoprotein substrates (may alter drug transport and absorption)
• Antihypertensive medications (may enhance blood pressure-lowering effects)
• 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)
• Drugs requiring bacterial glucuronidase activation in the gut (may compete for these enzymes)

Due to limited human clinical data, a definitive upper limit has not been established. Based on animal toxicity studies, doses up to 150-200 mg/kg body weight have been used without significant adverse effects, suggesting a relatively high safety margin. For human supplementation, doses exceeding 200 mg of scutellarein or 1000 mg of standardized herbal extract daily are not recommended without medical supervision due to potential drug interactions and limited long-term safety data.

It ‘s important to note that most safety data comes from studies on scutellarin (the glycoside form) or herbal extracts containing a mixture of flavonoids, rather than isolated scutellarein.

Scutellarein itself is not approved as a drug by the FDA and is not commonly available as an isolated supplement. Scutellaria baicalensis and Erigeron breviscapus extracts containing scutellarein or its glycoside scutellarin 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 scutellarein specifically.

Scutellarein is generally recognized as safe (GRAS) as a component of traditional herbal medicines when used in conventional amounts.

Eu: In the European Union, scutellarein is not approved as a medicinal product. Scutellaria baicalensis extracts containing scutellarein or 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 scutellarein or related extracts. Some EU member states may have their own regulations regarding traditional herbal medicinal products containing Scutellaria species.

Canada: Health Canada regulates Scutellaria baicalensis extracts containing scutellarein or 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. Isolated scutellarein is not specifically approved as a standalone ingredient.

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. Scutellarein as an isolated compound is not specifically regulated.

China: Scutellaria baicalensis (Huang Qin) and Erigeron breviscapus (Dengzhanxixin) are officially listed in the Chinese Pharmacopoeia as traditional Chinese medicines. Various formulations containing these herbs are approved for specific indications based on traditional use and modern research. Breviscapine, an extract of Erigeron breviscapus standardized for scutellarin content, is approved as a drug in China for the treatment of cerebrovascular diseases. Scutellarein as an isolated compound is primarily used in research rather than as an approved therapeutic agent.

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. Scutellarein as an isolated compound is not specifically regulated for therapeutic use.

High (as isolated compound) / Medium (as part of herbal extracts)

Isolated scutellarein is rarely available commercially for supplementation and is primarily sold as a research chemical at prices ranging from $300-$600 per 10-25 mg, making

it prohibitively expensive for regular supplementation. Standardized Scutellaria baicalensis extracts containing scutellarein 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. Erigeron breviscapus extracts standardized for scutellarin (which can be converted to scutellarein in the body) typically cost $1.00-$3.00 per day for basic extracts and $3.00-$7.00 per day for premium, highly standardized formulations or pharmaceutical-grade breviscapine.

The cost-effectiveness of scutellarein must be evaluated in the context of herbal extracts containing it, as isolated scutellarein is not practically available for regular supplementation due to its high cost and limited commercial availability. For neuroprotective effects, Erigeron breviscapus extracts standardized for scutellarin content may offer the best value, as they have been specifically studied for cerebrovascular conditions and contain relatively high concentrations of scutellarin, which can be converted to scutellarein in the body. For general anti-inflammatory and antioxidant benefits, Scutellaria baicalensis extracts offer good value due to their content of multiple complementary flavonoids including baicalin, baicalein, and wogonin, which work synergistically with scutellarein. Basic herbal extracts provide good value for general health maintenance and mild inflammatory conditions.

However, their effectiveness may be limited by variable content of active compounds and poor bioavailability. Premium extracts with standardized flavonoid content provide more consistent results but at a higher price point. For specific applications like neuroprotection in high-risk individuals (e.g., those with a history of stroke or cognitive decline), the higher cost of premium standardized extracts or pharmaceutical-grade preparations (where available) may be justified by the potential benefits. Enhanced delivery formulations such as nanoemulsions, liposomes, or SEDDS offer the best therapeutic potential due to significantly improved bioavailability (3-10 fold increase), potentially justifying their higher cost for specific health conditions.

When comparing the cost-effectiveness of extracts containing scutellarein to other botanical supplements with similar indications, they generally offer competitive value. For neuroprotective effects, Erigeron breviscapus extracts are comparable in cost and potentially superior in efficacy to many other herbal neuroprotectants. For anti-inflammatory and antioxidant benefits, Scutellaria baicalensis extracts are generally less expensive than many specialized botanical extracts with similar applications.

Pure scutellarein is relatively unstable compared to methoxylated flavones due to its tetrahydroxy structure, which increases its susceptibility to oxidation. When properly stored, isolated scutellarein may maintain stability for 1-2 years. Scutellarin (the glycoside form) is more stable than scutellarein and typically has a shelf life of 2-3 years when properly stored. Standardized herbal extracts containing scutellarein or scutellarin typically have a shelf life of 1-2 years from the date of manufacture.

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 pure scutellarein and can extend shelf life of extracts containing scutellarein or scutellarin. Protect from moisture, heat, oxygen, and light exposure, which can accelerate degradation. For research-grade pure scutellarein, storage under inert gas (nitrogen or argon) at -20°C is recommended for maximum stability.

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 rapid photodegradation due to the reactive hydroxyl groups, High temperatures (above 25°C) – accelerates oxidation and decomposition, Moisture – can promote hydrolysis and microbial growth, particularly in liquid formulations, Oxygen exposure – leads to oxidation, particularly of the hydroxyl groups, pH extremes – scutellarein is most stable at slightly acidic pH (5-6), Metal ions (particularly iron and copper) – can catalyze oxidation reactions, Enzymatic activity – may occur in improperly processed plant extracts, Incompatible excipients in formulations – certain preservatives or other ingredients may interact negatively with scutellarein, Repeated freeze-thaw cycles – can destabilize enhanced delivery formulations such as nanoemulsions or liposomes

Synthesis Methods

Natural Sources

Quality Considerations

Scutellarein 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 scutellarein to the traditional uses of these plants was unknown to ancient practitioners, it is now recognized as one of the bioactive compounds in these historically important medicinal materials. Scutellarein is primarily found in Scutellaria species (skullcaps) and Erigeron breviscapus, both of which have rich histories in traditional medicine. In Traditional Chinese Medicine (TCM), Scutellaria baicalensis (Huang Qin or Chinese skullcap) has been used for over 2,000 years.

It was classified as a cooling herb that clears heat, dries dampness, and eliminates toxins. 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, where it was recommended for treating abscesses, sores, and inflammatory conditions. During the Tang Dynasty (618-907 CE), Chinese skullcap was recognized for its ability to ‘clear heat and dry dampness.’ The famous physician Sun Simiao included detailed descriptions of its applications in his work ‘Qianjin Yaofang’ (Thousand Golden Prescriptions).

In the Ming Dynasty (1368-1644 CE), the renowned physician Li Shizhen further documented the medicinal properties of Scutellaria baicalensis in his monumental work ‘Bencao Gangmu’ (Compendium of Materia Medica), noting its effectiveness for ‘clearing heat from the upper burner’ and treating coughs with yellow phlegm, thirst, and irritability. 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. It was traditionally used to treat paralysis, rheumatism, gastritis, and cardiovascular diseases. Its use became more widespread in Chinese medicine during the mid-20th century, particularly for the treatment of cerebrovascular diseases.

In North America, Scutellaria lateriflora (American skullcap) was used by Native American tribes and later by European settlers as a sedative, anxiolytic, and anticonvulsant. It was particularly valued for treating nervous disorders, insomnia, and anxiety. In European herbal medicine, various Scutellaria species were used for similar purposes, though less prominently than in Asian traditions. Scutellarein was first isolated and characterized in the mid-20th century as part of the scientific investigation into the active components of these traditional medicinal plants.

It was identified as a tetrahydroxyflavone, a class of compounds that has attracted scientific interest due to their potent antioxidant and anti-inflammatory properties. Modern scientific interest in scutellarein began to grow in the late 20th and early 21st centuries as research revealed its neuroprotective, anti-inflammatory, and potential anticancer properties. It’s important to note that scutellarein is often found in plants as its glycoside form, scutellarin (scutellarein-7-O-glucuronide), which has been more extensively studied in modern research. The distinction between scutellarein and scutellarin was not recognized in traditional medicine, as these compounds were not isolated or characterized until modern times.

No meta-analyses specifically on scutellarein are currently available; most analyses focus on Scutellaria baicalensis extracts or scutellarin (the glycoside form) rather than isolated scutellarein.

Limited ongoing trials specifically investigating scutellarein; most research focuses on Scutellaria extracts or scutellarin rather than isolated scutellarein, Several preclinical studies investigating scutellarein’s potential in neurodegenerative diseases, particularly focusing on its neuroprotective properties in Alzheimer’s and Parkinson’s disease models, Research on novel delivery systems to enhance scutellarein’s bioavailability and targeted delivery, Investigations into scutellarein’s potential as an anticancer agent, particularly in combination with conventional therapies