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Helenalin
Helenalin
Helenalin
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Helenalin
Names
IUPAC name
(8αH)-6α-Hydroxy-4-oxo-10α-ambrosa-2,11(13)-dieno-12,8-lactone
Systematic IUPAC name
(3aS,4S,4aR,7aR,8R,9aR)-4-Hydroxy-4a,8-dimethyl-3-methylidene-3,3a,4,4a,7a,8,9,9a-octahydroazuleno[6,5-b]furan-2,5-dione
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
UNII
  • InChI=1S/C15H18O4/c1-7-6-10-12(8(2)14(18)19-10)13(17)15(3)9(7)4-5-11(15)16/h4-5,7,9-10,12-13,17H,2,6H2,1,3H3/t7-,9+,10-,12-,13+,15+/m1/s1 ☒N
    Key: ZVLOPMNVFLSSAA-XEPQRQSNSA-N ☒N
  • InChI=1/C15H18O4/c1-7-6-10-12(8(2)14(18)19-10)13(17)15(3)9(7)4-5-11(15)16/h4-5,7,9-10,12-13,17H,2,6H2,1,3H3/t7-,9+,10-,12-,13+,15+/m1/s1
    Key: ZVLOPMNVFLSSAA-XEPQRQSNBI
  • O=C/2O[C@@H]3C[C@H]([C@@H]1/C=C\C(=O)[C@@]1(C)[C@@H](O)[C@@H]3C\2=C)C
Properties
C15H18O4
Molar mass 262.305 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Helenalin, or (-)-4-Hydroxy-4a,8-dimethyl-3,3a,4a,7a,8,9,9a-octahydroazuleno[6,5-b]furan-2,5-dione, is a toxic sesquiterpene lactone which can be found in several plants such as Arnica montana and Arnica chamissonis Helenalin is responsible for the toxicity of the Arnica spp. Although toxic, helenalin possesses some in vitro anti-inflammatory and anti-neoplastic effects. Helenalin can inhibit certain enzymes, such as 5-lipoxygenase and leukotriene C4 synthase. For this reason the compound or its derivatives may have potential medical applications.[1][2]

Structure and reactivity

[edit]

Helenalin belongs to the group of sesquiterpene lactones which are characterised by a lactone ring. Beside this ring, the structure of helenalin has two reactive groups (α-methylene-γ-butyrolactone and a cyclopentenone group) that can undergo a Michael addition.[3][4] The double bond in the carbonyl group can undergo a Michael addition with a thiol group, also called a sulfhydryl group. Therefore, helenalin can interact with proteins by forming covalent bonds to the thiol groups of cysteine-containing proteins/peptides, such as glutathione. This effect can disrupt the molecule's biological function.[2] Addition reactions can occur because thiol groups are strong nucleophiles; a thiol has a lone pair of electrons.[5]

Chemical derivatives

[edit]

There are several derivatives of helenaline known within the same sesquiterpene lactone group; pseudoguaianolides. Most of these derivatives occur naturally, such as the compound dihydrohelenalin, but there are also some semi-synthetic derivatives known, such as 2β-(S-glutathionyl)-2,3-dihydrohelenalin.[1][2] In general, most derivatives are more toxic than helenalin itself. Among these, derivatives with the shortest ester groups are most likely to contain a higher toxicity.[6] Other derivatives include 11α,13-dihydrohelenalin acetate, 2,3-dehydrohelenalin and 6-O-isobutyrylhelenalin. The molecular conformation differs between helenalin and its derivatives, which affects the lipophilicity and the accessibility of the Michael addition sites. Poorer accessibility results in a compounds with lower toxicity.[citation needed] Another possibility is that a derivative lacking one of the reactive groups, such as the cyclopentenone group, may have a lower toxicity.[citation needed]

Some biochemical effects of helenalin

[edit]

Helenalin can target the p65 subunit (also called RelA) of the transcription factor NF-κB. It can react with Cys38 in RelA by Michael addition. Both reactive groups, α-methylene-γ-butyrolactone and cyclopentene, can react with this cysteine.[3] It was also found that helenalin can inhibit human telomerase, a ribonucleoprotein complex, by Michael addition. In this case also, both reactive groups of helenalin can interact with the thiol group of a cysteine and inhibit the telomerase activity.[7] Helenalin inhibits the formation of leukotrienes in human blood cells by inhibiting LTC4 synthase activity. Helenalin reacts with its cyclopentenone ring to the thiol group of the synthase.[2]

Metabolism

[edit]

Helenalin inhibits cytochrome P450 enzymes by reacting with thiol groups, resulting in inhibition of the mixed-function oxidase system. These effects are important for the cytotoxicity of helenalin. The levels of glutathione, which contains sulfhydryl groups, are reduced in helenaline-treated cells, further increasing the toxicity of helenalin. Depending on the dose of helenalin, thiol-bearing compounds such as glutathione may provide some protection to cells from helenalin toxicity. It was also seen that helenalin increase CPK and LDH activities in serum and that it inhibits multiple enzymes of the liver involved in triglyceride synthesis. Therefore, helenaline causes acute liver toxicity, accompanied by a decrease in cholesterol levels.[8]

Helenalin also suppresses essential immune functions, such as those mediated by activated CD4+ T-cells, by multiple mechanisms.[9]

In vitro anti-inflammatory and anti-neoplastic effects

[edit]

Helenalin and some of its derivatives have been shown to have potent anti-inflammatory and anti-neoplastic effects in vitro. Some studies have suggested that the inhibition by helenalin of platelet leukotriene C4 synthase, telomerase activity and transcription factor NF-κB contributes to helenalin's in vitro anti-inflammatory and anti-neoplastic activity[2][7][10] .[11][12] The dose used varied per study. There is currently no in vivo evidence regarding helenalin's anti-inflammatory and anti-tumour effects, if any. The efficacy of helenalin for treatment of pain and swelling, when applied topically, is not supported by the current available evidence at doses of 10% or lower. For doses higher than 10%, more research is required whether those remain safe and are more efficient than the current available medications.[13]

Application

[edit]

In former times, plant extracts containing helenalin were used as a herbal medicine for the treatment of sprains, blood clots, muscle strain and rheumatic complaints.[9] Currently helenalin is used topically in homeopathic gels and microemulsions. Helenalin is not FDA-approved for medical application.[14]

Toxicity

[edit]

When applied topically on humans, helenalin can cause contact dermatitis in sensitive individuals. However, it is considered generally safe when applied this way. Oral administration of large doses of helenalin can cause gastroenteritis, muscle paralysis, and cardiac and liver damage. The toxicity of helenalin was studied in mammalian species such as mice, rat, rabbit and sheep, where the oral LD50 of helenalin was established between 85 and 150 mg/kg.[15][16] It was shown in a mouse model that helenalin caused reduced levels of cholesterol. In a rat model, alcohol hepatic injury was prevented by helenalin administration.[8] Parenteral administration showed a higher toxic effect when compared to oral administration.[17][18]

Pharmacology

[edit]
See also: Arnica montana § Medicinal use

Helenalin has a variety of observed effects in vitro including anti-inflammatory and antitumour activities.[19] Helenalin has been shown to selectively inhibit the transcription factor NF-κB, which plays a key role in regulating immune response, through a unique mechanism.[20] In vitro, it is also a potent, selective inhibitor of human telomerase[7]—which may partially account for its antitumor effects—has anti-trypanosomal activity,[21][22] and is toxic to Plasmodium falciparum.[23]

Animal and in vitro studies have also suggested that helenalin can reduce the growth of Staphylococcus aureus and reduce the severity of S. aureus infection.[24]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Helenalin

View on Grokipedia
from Grokipedia
Helenalin is a , a primarily isolated from the flowers of and other species in the family, such as plants. With the molecular C15H18O4 ( 262.30 g/mol; CAS 6754-13-8), it features reactive exomethylene and α,β-unsaturated carbonyl groups that enable its biological interactions. Known for its potent effects, helenalin has been used in traditional folk medicine for centuries to treat minor injuries and , though its therapeutic potential is constrained by . The compound's primary mechanism of action involves selective inhibition of the transcription factor NF-κB, achieved by direct alkylation of the p65 subunit through Michael-type addition to its cysteine sulfhydryl groups. This modification prevents NF-κB from binding to DNA without affecting IκB degradation or nuclear translocation, leading to downregulation of proinflammatory cytokines like IL-1, IL-6, and TNF-α. In addition to anti-inflammatory properties, helenalin demonstrates in vitro antineoplastic activity by inducing apoptosis and inhibiting telomerase, as well as antitrypanosomal effects with IC50 values as low as 0.05 μM against Trypanosoma species. The total sesquiterpene lactone content in Arnica montana flowers, including helenalin and its derivatives, typically ranges from 0.4% to 0.6%, as standardized by the European Pharmacopoeia, and helenalin concentrations up to 3% dry weight in Helenium species. However, its bitterness and toxicity—responsible for the poisonous nature of Arnica—limit safe use, with oral LD50 values of 85–150 mg/kg in mammals and potential for allergic reactions in humans. Ongoing research, including 2023 studies on its anti-cancer potential in breast cancer cell lines, explores synthetic analogs to harness its benefits while mitigating these risks for applications in anti-inflammatory and anticancer therapies.

Chemical Properties

Structure

Helenalin is a pseudoguaianolide characterized by a fused bicyclic consisting of a seven-membered ring and a five-membered ring, along with an α-methylene-γ-lactone moiety and a cyclopentenone . Its molecular formula is C15H18O4C_{15}H_{18}O_4, with a of 262.305 g·mol−1^{-1}. The IUPAC name for helenalin is (3aS,4S,4aR,7aR,8R,9aR)-4-hydroxy-4a,8-dimethyl-3-methylidene-3,3a,4,4a,7a,8,9,9a-octahydroazuleno[6,5-b]furan-2,5-dione, reflecting its specific at six chiral centers (positions 3a, 4, 4a, 7a, 8, and 9a). Helenalin exists in polymorphic forms that differ primarily in their hydrogen-bonding patterns and molecular packing arrangements within the lattice.

Reactivity

Helenalin exhibits significant chemical reactivity primarily due to its electrophilic functional groups, which enable interactions with biological nucleophiles. The molecule contains an α-methylene-γ-butyrolactone moiety and an α,β-unsaturated cyclopentenone group, both serving as Michael acceptors that facilitate conjugate additions. The reactivity of helenalin is dominated by the Michael addition mechanism, wherein these electrophilic sites undergo 1,4-addition with thiol-containing nucleophiles, such as residues in proteins or (GSH). This process forms stable covalent adducts, with the addition to the α-methylene-γ-butyrolactone being irreversible, while the cyclopentenone addition is reversible under physiological conditions. The general reaction for this Michael addition can be represented as: Helenalin+R-SH→Helenalin-S-R (adduct)\text{Helenalin} + \text{R-SH} \rightarrow \text{Helenalin-S-R (adduct)} where the exocyclic methylene of the or the β-carbon of the enone accepts the in a 1,4-fashion, leading to saturation of the double bond and thioether formation. Helenalin's , modulated by its rigid molecular conformation and lack of polar substituents, enhances its ability to permeate cell membranes, thereby facilitating access to intracellular targets for these reactive interactions.

Derivatives

Helenalin derivatives include both naturally occurring and semi-synthetic compounds that modify its core pseudoguaianolide , primarily through saturation of double bonds or conjugation with other molecules. A key natural derivative is dihydrohelenalin (also known as 11α,13-dihydrohelenalin), which features saturation of the exocyclic at positions C-11 and C-13 compared to the parent helenalin, reducing reactivity at that site while retaining the overall framework. This compound occurs alongside helenalin in flowers, often as ester forms such as dihydrohelenalin acetate. Semi-synthetic derivatives encompass conjugates like 2β-(S-)-2,3-dihydrohelenalin, formed via Michael-type addition of 's group to the α,β-unsaturated carbonyl in the dihydrohelenalin , resulting in a more polar at the 2β position. Additionally, helenalin esters, such as the , involve at the hydroxyl group at C-4, with chain lengths varying from short () to longer (tiglate or isovalerate). Structural modifications like esterification at hydroxyl sites generally increase , enhancing membrane permeability, while hydrogenation of double bonds, as in dihydrohelenalin, decreases electrophilic reactivity. Regarding , shorter ester chains (e.g., and isobutyrate) exhibit higher than helenalin itself in cell lines like L1210 cells, whereas longer chains (e.g., tiglate) reduce , likely due to steric hindrance and altered . However, comprehensive data remain limited for many derivatives, particularly regarding long-term effects and specific organ impacts beyond sensitization potential.

Biological Sources and Biosynthesis

Natural Occurrence

Helenalin, a sesquiterpene lactone, occurs naturally primarily in species of the genus Arnica and Helenium within the Asteraceae family, with significant concentrations found in Arnica montana (European arnica), Arnica chamissonis (meadow arnica), and various Helenium species such as H. autumnale. These plants are perennial herbs native to temperate regions, where A. montana inhabits nutrient-poor, acidic grasslands and meadows in mountainous areas of Europe, often at elevations between 600 and 2,500 meters, while A. chamissonis grows in similar open, moist meadows across North America. Helenium species are native to North America, with helenalin content reaching 0.5–3% dry weight in flowers. Within these plants, helenalin concentrations are highest in the flower heads, ranging from 0.2% to 1% of dry weight for helenalin and its derivatives in , whereas rhizomes and roots contain only trace amounts or none at all. In , levels are higher, up to 3% dry weight. The compound's levels vary significantly by plant part and are influenced by ecological parameters, including soil composition (e.g., siliceous versus substrates), altitude, , and . For example, studies have shown a positive between higher altitudes and elevated helenalin content in A. montana, likely due to stress responses in harsher environments. Helenalin is typically isolated from the flowers of and species using solvent extraction methods, such as with or other organic solvents, to yield the for further analysis or use. As a , it contributes to the plant's against herbivores and pathogens.

Biosynthesis

Helenalin, a pseudoguaianolide , is biosynthesized in such as from (FPP), which is produced via the mevalonate (MVA) pathway in the or the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway in plastids. FPP is formed by the condensation of (DMAPP) and isopentenyl diphosphate (IPP) catalyzed by farnesyl diphosphate (FDS). This precursor undergoes cyclization by synthases (STPSs), such as germacrene A (GAS), to form a germacrane precursor, which serves as the foundational for pseudoguaianolides like helenalin. Subsequent rearrangements lead to the characteristic pseudoguaianolide framework. Key biosynthetic steps include the initial cyclization of FPP to germacrene A, followed by oxidation via germacrene A (GAO, a from the CYP71A2-8 family) to introduce hydroxyl groups and facilitate ring modifications. Further oxidations and hydroxylations by enzymes from the CYP71BL subfamily form the α-methylene-γ- ring, while additional modifications by alcohol dehydrogenases, reductases, and acyltransferases introduce the exocyclic methylene and ester functionalities typical of helenalin derivatives. The introduction of the exocyclic methylene occurs through oxidative processes that activate the for . Although partial involvement of germacrene synthase has been identified, the full enzymatic sequence for helenalin remains unelucidated. Biosynthesis is localized primarily in the flower heads of Arnica species, with high concentrations in glandular trichomes of the corolla, pappus calyx, and ovary, where sesquiterpene lactones colocalize with inulin storage vacuoles. Content increases progressively from flower buds to full maturity, reflecting developmental regulation. Regulation of helenalin production is elicited by biotic and abiotic factors, including jasmonic acid (JA) at concentrations of 0.25–1 mg/L, which boosts sesquiterpene lactone yields by up to 66% in tissue cultures via JAZ-MYC signaling pathways; chitosan at 50–100 mg/L, increasing levels fivefold and favoring helenalin esters; and red light at 30–150 µmol m⁻² s⁻¹, enhancing accumulation by 60–300%. Recent studies from 2020–2025 demonstrate that these elicitors and stress conditions, such as low light or pathogen exposure, upregulate helenalin derivatives, promoting protective responses in young tissues and shifting metabolic profiles toward pseudoguaianolides under environmental stress.

Pharmacological Effects

Anti-inflammatory Effects

Helenalin demonstrates potent anti-inflammatory activity primarily through targeted inhibition of key signaling pathways in inflammatory cells. A primary mechanism involves the covalent of the , which orchestrates the expression of numerous pro-inflammatory genes. Helenalin alkylates residues, potentially including Cys38, on the p65 () subunit via Michael-type addition, thereby preventing NF-κB's DNA binding and subsequent activation of production, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This NF-κB inhibition occurs downstream of IκB degradation and nuclear translocation, effectively blocking NF-κB-driven transcription in response to diverse stimuli such as TNF-α or phorbol esters. In vitro studies across cell models, including T-cells, B-cells, epithelial cells, and macrophages, show reduced inflammatory responses, with IC50 values for p65 DNA binding inhibition ranging from 2.5 to 5 μM in electromobility shift and surface plasmon resonance assays. Helenalin also suppresses the 5-lipoxygenase (5-LOX) pathway by alkylating groups on enzymes involved in biosynthesis. In polymorphonuclear granulocytes and platelets, it inhibits 5-LOX activity (IC50 ≈ 9 μM after 60-minute preincubation) and C4 synthase (IC50 ≈ 12 μM), thereby curtailing the production of pro-inflammatory that contribute to conditions like and allergic responses. This dual action on and 5-LOX pathways underscores helenalin's broad potential to dampen acute at multiple levels. Although helenalin's thiol reactivity underpins these effects, as detailed in its chemical properties, in vivo and clinical evidence remains limited, with studies confined largely to models. Preliminary indications suggest potential for topical application in models, where localized delivery could exploit its potency while minimizing systemic toxicity.

Anti-neoplastic Effects

Helenalin exhibits anti-neoplastic effects primarily through inhibition of and induction of in cancer cells. It alkylates the catalytic subunit of , thereby reducing human (hTERT) activity and expression, which limits the proliferative capacity of tumor cells. For instance, in the T47D cell line, helenalin significantly downregulated hTERT gene expression in a dose-dependent manner, with significant inhibition observed at 5 μM after 48 hours of treatment. This mechanism has also been demonstrated in hematopoietic cancer cells, where helenalin potently suppressed activity by directly interacting with the enzyme's residues. In addition to telomerase inhibition, helenalin promotes in various types via blockade of signaling—sharing this pathway with its anti-inflammatory actions—and by generating (ROS). The inhibition disrupts prosurvival pathways, sensitizing cells to death signals even in cases of Bcl-2 overexpression, as seen in human leukemic . Concurrently, helenalin elevates intracellular ROS levels, which trigger mitochondrial dysfunction and activation; ROS scavengers like N-acetylcysteine attenuated this in , confirming the dependency. In cells (DU145 and PC-3 lines), helenalin further targeted 1 (TrxR1), amplifying ROS-mediated and cell cycle arrest at G2/M phase, with effects prominent at 5-10 μM concentrations. Helenalin demonstrates in vitro cytotoxicity against multiple cancer cell lines, including those from leukemia (e.g., HL-60, Tmolt3), breast (e.g., T47D), and prostate (e.g., DU145), with IC50 values typically ranging from 0.5 to 10 μM. This potency arises from its ability to selectively target rapidly dividing cancer cells over normal ones, potentially extending to cancer stem cells due to its disruption of key survival pathways common in these populations. Derivatives such as helenalin acetate exhibit enhanced potency and improved solubility compared to the parent compound, facilitating better cellular uptake and stronger inhibition of transcription factors like C/EBPβ in tumor cells. As of 2025, helenalin's anti-neoplastic effects remain confined to preclinical studies, with no ongoing or completed clinical trials reported for cancer treatment.

Other Effects

Helenalin exhibits anti-trypanosomal activity by inhibiting key parasite enzymes through its reactivity with thiol groups, with in vitro IC50 values below 10 μM against Trypanosoma species; specifically, it shows an IC50 of 0.051 μM against T. brucei rhodesiense and 0.695 μM against T. cruzi. Similarly, helenalin demonstrates anti-malarial effects against the asexual blood stages of Plasmodium falciparum, with helenalin and related pseudoguaianolide sesquiterpene lactones displaying potent in vitro activity. Regarding antimicrobial properties, helenalin reduces growth in vitro within bovine mammary epithelial cells and limits bacterial proliferation in vivo in mouse models of mammary gland infection, leading to significantly fewer recoverable bacteria without causing host cell apoptosis. Helenalin also possesses immunosuppressive effects, suppressing essential functions of activated CD4+ T cells, including cytokine production and proliferation, positioning it as a candidate for treating T cell-mediated immune disorders. In terms of enzyme inhibition, helenalin partially inhibits human enzymes, particularly and , during its in liver microsomes, with inhibitory effects observed at micromolar concentrations.

Metabolism and Toxicity

Metabolism

Helenalin undergoes phase I primarily through enzymes in hepatic microsomes, with and identified as the main isoforms responsible in humans, alongside and extrahepatic CYP2A13. This process yields oxidative metabolites such as 14-hydroxyhelenalin in human liver microsomes and 9-hydroxyhelenalin in rat microsomes, along with reduced metabolites in cytosolic fractions. Notably, helenalin acts as a mechanism-based inhibitor of these enzymes, particularly (IC50 = 18.7 µM) and (IC50 = 62.6 µM), which may impair the of co-administered xenobiotics. In phase II metabolism, helenalin readily undergoes conjugation with (GSH) via glutathione S-transferase (GST) enzymes, forming adducts such as the 2β-(S-glutathionyl)helenalin through Michael addition at the α-methylene-γ-lactone moiety. This reaction, which can occur spontaneously or enzymatically (as demonstrated with horse liver GST), depletes intracellular GSH levels and contributes to the compound's electrophilic reactivity in biological systems. Although GST catalysis does not significantly accelerate the conjugation compared to non-enzymatic pathways, the resulting adducts inhibit GST activity, potentially exacerbating . In vitro studies using , pig, and liver microsomes have elucidated the of helenalin derivatives like helenalin and 11α,13-dihydrohelenalin , revealing predominant thiolation via GSH and conjugation (yielding up to four mono- and di-GSH adducts for helenalin ), alongside phase I hydroxylations but no detectable . These pathways highlight species-specific differences, with microsomes showing higher metabolic efficiency than ones. Additionally, acute exposure in rodents elevates liver enzymes such as ALT, indicating rapid hepatic impact during metabolism. Extensive liver conjugation suggests potential biliary and renal excretion routes, consistent with glutathione-mediated metabolism observed in related sesquiterpene lactones.

Toxicity

Helenalin exhibits significant acute toxicity via oral administration, with an LD50 ranging from 85 to 105 mg/kg in rodents such as mice and rats. This exposure leads to symptoms including gastroenteritis characterized by vomiting and diarrhea, progressive paralysis, and damage to hepatic and renal tissues, as evidenced by elevated serum markers like alanine aminotransferase and blood urea nitrogen. Topical application of helenalin can induce in sensitive individuals at concentrations exceeding 10%, manifesting as redness, itching, and eczematous reactions. However, formulations at or below 10% in gels are generally considered safe for external use, with low incidence of adverse skin effects when applied to intact skin. Chronic exposure to helenalin results in damage to lymphatic tissues, including reduced and weights, alongside that increases susceptibility to infections due to decreased counts. The primary mechanisms underlying this toxicity involve depletion of (GSH) through conjugation, leading to protein via Michael addition to residues and subsequent . This GSH depletion is exacerbated by metabolic conjugation processes. Human cases of helenalin are rare and typically arise from misuse of Arnica-containing products, such as internal , resulting in gastrointestinal distress and . No fatalities have been reported from helenalin exposure after , reflecting improved awareness and restricted use. Regulatory bodies have imposed strict limits on helenalin due to its profile; it is not approved by the FDA for internal use, classified as unsafe for . The (EMA) permits its presence in herbal products only for external application, with defined limits on content to minimize risks.

Applications

Historical Uses

Helenalin, a sesquiterpene lactone primarily found in plants of the genus Arnica, particularly Arnica montana, has been utilized in traditional medicine through the application of these plants for centuries. In European folk medicine, Arnica montana was employed topically to treat sprains, bruises, and rheumatism, with records dating back to the medieval period and continuing into the 18th century. Native American communities also incorporated various Arnica species, such as Arnica cordifolia, into their healing practices for similar purposes, including the treatment of trauma, cuts, bruises, and sore throats. By the , preparations gained formal recognition in pharmacopeias across and , where diluted tinctures were introduced in homeopathic medicine for relief associated with injuries and . These homeopathic formulations, often highly diluted to minimize risks, were applied externally or taken orally in low doses to alleviate muscle and . Helenalin was first isolated in 1949 from the flowers of . It was subsequently identified in Arnica montana flowers during the mid-20th century, marking a shift toward scientific investigation of its active components. Initial studies in the 1960s explored its anti-inflammatory potential, building on the empirical uses of extracts. However, concerns over toxicity led to the abandonment of oral Arnica use by the mid-20th century, restricting applications to topical forms to avoid adverse effects like and cardiac issues.

Modern Applications

In modern applications, helenalin is primarily utilized in topical formulations derived from extracts, such as gels and creams, for the symptomatic relief of muscle and pain, bruises, and associated with blunt injuries. These products typically contain low concentrations of lactones, including helenalin at levels of 0.3–1.0% in the herbal substance, ensuring external use only to minimize toxicity risks. Homeopathic preparations incorporating helenalin are commonly available in for similar indications, including rheumatic complaints and post-traumatic swelling. Ongoing preclinical explores helenalin's potential as an adjunct in , particularly for its anti-neoplastic effects in cell lines like T47D , where it inhibits and promotes . As of 2025, no clinical trials investigating helenalin for are registered, limiting its advancement to therapeutic use. To address helenalin's poor aqueous , nanoparticle-based delivery systems, such as nano-encapsulated forms and β-cyclodextrin complexes, have been developed in laboratory settings to enhance and targeted efficacy against tumor cells. The European Medicines Agency (EMA) permits low-dose herbal preparations of Arnica montana containing helenalin for traditional topical use under well-established or traditional registration, but systemic administration remains unapproved due to toxicity concerns. Challenges in broader application stem from helenalin's hepatotoxic and allergenic profile, prompting studies on derivatives like esters to potentially reduce toxicity while retaining bioactivity; for instance, certain acyl esters exhibit lower cytotoxicity in vitro compared to the parent compound. Future developments may include helenalin in anti-malarial combinations, given its demonstrated in vitro activity against Plasmodium falciparum blood stages at micromolar concentrations.

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