Maidenhair Fern Leaf

Traditional applications of Maidenhair fern as single medicine
Oral application of the fronds decoction was reported to be useful for cleansing respiratory system, dyspnea, asthma, coryza and chest pain in the field of respiratory system (4). Ancient physicians also applied the eye drop in order to control the fistula lacrymalis condition (6). Oral powders of Maidenhair fern were extensively administrated for gastrointestinal disorders such as jaundice, diarrhea and abdominal cramps (7). Maidenhair fern was reported as a headache-preventing agent. It was also supposed to be effective for dissolving the kidney calculi and as a diuretic agent in oral administration (4, 7). A. capillus-veneris was also introduced as a powerful anti-inflammatory agent. Therefore, it was applied on fistula in the form of ointment. Persian physicians also administrated oral decoction for female genital disorders such as amenorrhea (5). The plant also helps child birth and extracting placenta with oral administration of decoction (4, 7). Maidenhair fern is a potent hair tonic that treats alopecia and helps hair growth and it is useful for dandruffs (4–7).

Traditional applications of Maidenhair fern in multi-herbal formulations
Maidenhair fern has been extensively used in multi-herbal prescriptions for the treatment of many diseases such as respiratory, urogenital and dentistry diseases. The main multi-herbal formulations of the species along with their indications and dosage forms have been described in Table 1.

Table 1:
The main multi-herbal formulations containing Maidenhair fern according to ITM

Organs Action(s) Components Dosage form
Central nervous system Anti Alzheimer, Brain tonic Liquorice, Sweet Violet, Damask Rose, Lavender, Peony, Borage, Fennel, Celery, Marshmallow, Stavesacre, Assyrian Plum, Honey Syrup (19)
Treatment of Epilepsy, Mania and Headache Lavender, Liquorice, Borage, Fennel, Celery, Marshmallow, Sweet Violet, Damask Rose, Stavesacre, Assyrian Plum Syrup (18)
Dentistry Dental analgesic 1. Liquorice, Borage flower
2. Lavender, Fumitory, Jujube, Black Nightshade aromatic water 1. Oral decoction, Mouthwash
2. Oral, decoction (19)
Dental tonic Frankincense, Long Aristolochi, Sweet Violet, Sandalwood Dental Powder (17)
Hair Anti hair loss 1. Chinaberry, Myrrh, Indian Gooseberry, Myrtle oil
2. Rockrose, Wormwood, Chio Gum
3. Myrtle, Celery seed, Radish oil Lotion, Liniment (18,19)
Hepatic System Hepatitis Fenugreek, Flax, Liquorice, Marshmallow, Common Mallow, Hyssop, Fig, Stavesacre Syrup (16)
Jaundice Romanwormwood, Oregano, Poley, Chamomile, Feverfew, Dill, Common Wood Sorrel, Citron Face wash (17)
Respiratory system Anti common cold, Antipyretic Liquorice, Quince, Sweet Violet, Cucumber seed mucilage Oral decoction (19)
Antiasthmatic Mango mucilage, Liquorice Aromatic water (18)
Antiasthmatic, Antitussive Flax, Hyssop, Orris, Borage, Fennel, Liquorice, Fig, Stavesacre Oral decoction (18)
Antitussive 1. Liquorice, Hyssop, Sweet Violet syrup
2. Fig, Stavesacre, Liquorice, Hyssop, Orris root
3. Fennel, Celery, Liquorice, Sweet Almond kernel
4. Myrtle, Melon, Liquorice, Gum Arabic
5. Fennel, Celery, Liquorice, Bitter almond kernel, Flax mucilage 1.Oral decoction (19)
2. Oral decoction (17)
3. Pill (18)
4. Tablet (18)
5. Pill, Tablet (17)
Pleural analgesic Fennel, Stavesacre, Damask Rose in combination with Honey Oral decoction (19)
Pleural analgesic, Chest pain reliever Pennyroyal, Anise, Liquorice, Fennel Oral decoction (19)
Respiratory tract tonic, Antitussive Liquorice, Assyrian Plum, Stavesacre, Hyssop, Anise, Marshmallow, Common Mallow, Orris Aromatic water (18)
Treatment of Pharyngitis Common Dodder, Chamomile, Marshmallow, Radish, Fig, Celery Gargle (19)
Urogenital system Abortive Cretan dittany, Savin White Lupin, Pennyroyal Oral decoction (18)
Anti Cystolithiasis Caltrop, Horse gram, Rusty-back, Fig Oral decoction (19)
Anti Nephrolithiasis Melon, Willd Caraway, Ajwain, Galingale, Celery, Radish seed, Bitter Almond kernel Oral decoction (16)
Anti nephrolithiasis and Cystolithiasis 1. Horse gram, Caltrop, Melon, Fennel, Grape
2. Caltrop, Chamomile, Sweetclover, Oregano, Celery, Wild Cabbage, Dill, Marshmallow 1. Syrup (19)
2. Sitz bath (17)
Cystitis and Nephritis Senna, Common Polypody, Sweet Violet, Cucumber, Chicory, Plum, Jujube, Fumitory, Golden Shower Oral decoction (19)
Dysuria Caltrop, Chamomile, Dill, Celery, Sweetclover, Radish, Wild Cabbage, Marshmallow, Flax, Fenugreek, Sweet Violet Sitz bath (19)
Emmenagogue Cretan dittany, Fennel, Rue Oral decoction (18)
Emmenagogue, Abortive Golden Shower, Cretan dittany Oral decoction (18)
Induction of parturition Golden Shower, Caltrop, Melon, Savin, Cretan dittany, Marshmallow, Garden asparagus Oral decoction (18)
Nephralgia treatment Wild Carrot, Caltrop, Hyssop Oral decoction (19)
Gonorrhea Anise, Celery, Sweet Violet, Borage, Caltrop, Winter Cherry, Cucumber Syrup (18)
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Pharmacological effects
Anti-diabetic activity
The anti-diabetic effect of aqueous and methanol extracts of Maidenhair fern was assessed through streptozocin-induced diabetic rat model. Improvement in the fasting blood sugar exhibited that the species has very good anti-diabetic effect with low side effects. The presence of flavonoids and tannins may be responsible for the anti-diabetic effect (20). Another research exhibited significant rise in rat’s body weight and amylase enzyme and reduction in the blood glucose. The ability of the plant to gain weight is because of its repair capacity on hepato-renal damaged cell. Besides, increase in serum amylase is due to insulin-like constituents in the species which affect pancreas activity for amylase secretion (21). Besides, it was declared that the species displayed antihyperglycemic property comparable to acarbose as reference drug (22).

Neuropharmacological activities
Neuropharmacological activities of the plant ethanoic extract were evaluated by using various methods. The plant revealed significant anticonvulsant effect through prolonging the onset of action and reduction in the period of seizures in PTZ-induced convulsion model, in addition by decrease in the time of different phases of seizure through MES-induced seizure method.

In mice forced swim assay, the species displayed depressant property by prolonging the immobility time. The species was not demonstrated remarkable skeletal muscle relaxation as well (23).

Hypocholesterolemic effect
The hypocholesterolemic effect from water extract of A. capillus-veneris was evaluated by using high cholesterol diet (HCD) fed model in rats. The results exhibited potent reduction of total cholesterol (TC), LDL and VLDL serum levels with no effect on HDL level. Moreover, atherogenic index of TC/HDL was approximately normalized in rats that treated with A. capillus-veneris (24).

Antiobesity effect
Aerial parts water extract of the herb exhibited phospholipase inhibitory effect through an in vitro model which was comparable to orlistat. Chlorogenic acid is also reported as the most responsible phytoconstituent (22).

Goitrogenic and anti-thyroidal effects
It has been proven that after using the plant, thyroid gland weight generally decreased, although thyroid peroxidase action, antioxidant enzymes, T4 and T3 serum levels increased in animals; however TSH serum level decreased strongly (25).

Antibacterial and antifungal activities
The antibacterial activity of Maidenhair fern against multidrug resistant (MDR) bacteria strains was evaluated through disc diffusion method. Leaves methanol extract of the species displayed maximum zone of inhibition against Providencia, Klebsiella pneumoniae, Shigella, Vibrio cholera, Staphylococcus aureus, Proteus vulgaris and Salmonella typhi. Stem methanol extract was very potent against Escherichia coli, K. pneumonia and S. typhi. Leave water extract of the species was very potent against all bacteria strains but its stem water extract revealed minimum ZI against E. coli, K. pneumonia, S. typhi, Shigella, Proteus vulgaris and Providencia (26). In another study, the antibacterial activities of A. capillus-veneris methanolic extract against S. aureus, E. coli, and Helicobacter pylori has been proven (27). In a research, crude and phenolic extracts of gametophyte and sporophyte of the plant were assessed for antibacterial properties. Antibacterial effect of gametophytic part of the plant was more significant. Gram-positive species like Bacillus subtilis displayed more susceptibility to both extracts (28). Moreover, the ethanolic extract of Maidenhair fern aerial parts have no antimicrobial capacities against three pathogen bacteria including E. coli, Staphylococcus aureus and Pseudomonas aeruginosa (29). In another research, methanolic extracts of four important Adiantum species including A. capillus-veneris, A. peruvianum, A. venustum and A. caudatum were evaluated for antibacterial and anti-fungal effects. Among these species A. capillus-veneris and A. venustum showed potent antibacterial properties. Besides, the antibacterial and fungal activities of leaves, stems, and roots were evaluated. Different extracts of all used parts displayed potent antibacterial and anti-fungal properties (30).

Wound healing property
During an in vitro study, wound healing property of A. capillus-veneris was evaluated. The water extract of the plant improved angiogenesis significantly by using both capillary-like tubular formations and proliferation of endothelial cells. Besides, aqueous and butanol fractions revealed significant protection against damage to fibroblasts by oxygen free radicals (31). In another research, an ointment that consists of Maidenhair fern, Aloe vera, Henna and Myrrha cured wounds in diabetic rats (32).

Anti testosterone-induced hair loss effect
The hair growth- promoting effect of ethanolic extract of Maidenhair fern was evaluated through testosterone-induced alopecia model in mice. The results revealed considerable increase in follicular density and anagen/telogen ratio (33).

Antioxidant activity
The antioxidant capacity of ultrasonic-assisted flavonoid extract of the plant has been evaluated. In vitro assays were done through DPPH, scavenging capacity of superoxide anion, chelating capability of ferrous ion and reducing power tests. In vivo examination was done by using acute mice liver injury experiment. The results exhibited more potent antioxidant activity of the species than some synthetic antioxidants such as BHT, EDTA, and ascorbic acid. In vivo evaluation displayed significant decrease in superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) levels and notable increase in malondialdehyde (MDA) levels (34). In another in vitro investigation, ethanolic extract of A. capillus-veneris leaves has assessed against hydrogen peroxide-induced oxidative damage in peripheral blood lymphocytes. The results demonstrated inhibition of lipid peroxidation and increase in the level of antioxidant enzymes including SOD, CAT, Gpx and glutathione content (35). During an in vitro study, antioxidant activity of the plant essential oil was confirmed through DPPH assay. Antioxidant property of the essential oil is because of phytoconstituents such as carvone, carvacrol, and thymol (9). In addition, A. capillus-veneris and M. punctatum were compared and reported that the rises in the malondialdehyde levels and antioxidant enzymes including superoxide dismutase and glutathione peroxidase in M. punctatum were more potent (36).

Urinary tract effect
The efficacy of A. capillus-veneris water extract was assessed on urinary tract. The result exerted inhibition effect on all tested bacterial species in this experiment. Systemic Candida albicans infection model was employed in mice to assess the protective activity of the plant. It also reduced the colony-forming units (CFU) of C. albicans in the spleen and improved the renal pathological characteristics. Besides, it displayed double effects on diuresis activity. The low dosage generally raised the urinary output and high dose significantly reduced the urinary output. A. capillus-veneris can be used for treatment of urinary tract infection (UTI) (37). In another research, hydroalcoholic extract of A. capillus-veneris was evaluated for anti-calcium oxalate urolithiasic property by male rats. The results revealed significant decrease in the number of crystals and reduction in the serum level of calcium, phosphorous and blood urea (38). They also confirmed this effect during an in vitro study. The plant restrained the crystallization, crystal aggregation, and reduction in the number and the sizes of crystals (39).

Anti-inflammatory activity
The ethyl acetate fraction of the plant ethanolic extract has displayed significant anti-inflammatory activity related to the inhibition of NO release and reducing in TNF-α level. Triterpenes may play chief role in the anti-inflammatory property of the plant (40). Moreover, during an in vitro study, the anti-inflammatory activity of the plant ethanolic extract was assessed through lipopolysaccharide-induced prostaglandin E2 generation in RAW 264.7 macrophage and interleukin 6 and tumor necrosis factor generation in the human monocyte model. The plant notable anti-inflammatory property is because of suppressing effect on nuclear factor kappa B activation, due to inhibitory effect on the production of inflammatory cytokines (41). In another investigation, two triterpenoids including 30-normethyl fernen-22-one and 4-α- hydroxyfilican-3-on that isolated from fronds ethanolic extract presented potent anti-inflammatory activity by using carrageenan-induced hind paw edema test in rat (12).

Analgesic and antinociceptive activities
The analgesic effect of the ethyl acetate fraction of the ethanolic extract from Maidenhair fern has been confirmed through tail-flick and writhing methods (40). Similar investigation confirmed powerful analgesic effect of Maidenhair fern through hot plate and tail immersion tests in mice (23). In addition, 4-α- hydroxyfilican-3-on that isolated from ethanolic extract of the plant showed significant anti nociceptive activity in writhing test (12).

Antidiarrheal and antispasmodic activities
In a research, the crude extract of A. capillus-veneris dried leaves was evaluated for antidiarrheal and antispasmodic capacities. Antidiarrheal effect was proved through castor oil-induced diarrhea in mice model. Furthermore, inhibitory effect on K+-induced contraction was seen in isolated rabbit jejunum preparation that confirmed the antispasmodic activity of the plant (42).

Anti-asthmatic activity
The anti-asthmatic effect of the ethanolic extract from A. capillus-veneris leaves was confirmed through histamine aerosol-induced asthma in guinea pig. It should be noted that the herb has been traditionally used as anti-asthmatic agent (43).

Detoxification activity
Crude extract of Maidenhair fern has demonstrated powerful protection through bisphenol A-induced reproductive system toxicity in rats (44). Besides, the ethanol extract of the plant at 500 mg/kg doses after 14 d therapy, revealed remarkable nephroprotective activity against cisplatin-induced nephropathy (45).

Toxicity and adverse reactions:
During an in vitro study, the effects of the ethanolic and aqueous extracts of maidenhair fern on aryl hydrocarbon hydroxylase (AHH) and epoxide hydrolase (EH) enzyme activities, which are responsible for accelerating conversion of carcinogenic compounds like poly aromatic hydrocarbons to active components, were assessed. Both plant extracts revealed no inhibitory effect on AHH and EH enzymes (46).

Toxicity study of Maidenhair fern ethanolic extract was done in rat. The results exhibited behavioral reactions in rats at the dose of 300 mg/kg. But no mortality was seen after 72 h (40).

Crude extract of Maidenhair fern at 1, 3 and 7 g/kg was administrated orally in mice. No sign of acute toxicity including seizure, piloerection and restlessness were reported after 6 h. Besides, after 24 h no mortality was seen in mice (42).

Acute oral toxicity studies of the aqueous and methanolic extracts were done in rat. Acute dosage was 2000 mg/kg as single dose. After first 30 min, 4 h and 24 h after administration, main changes in behavior and death were evaluated. Both extracts exhibited no major changes in behavior and no lethality as well (20).

For evaluation of acute toxicity, ethanol extracts of the species at the oral doses of 1000 and 2000 mg/kg were administrated to mice. After 24 h no sign of behavioral changes or mortality was seen (25). However, the plant should not be used during lactation period because of no available data. The plant is also contraindicated in pregnant women (3).

According to ITM, Maidenhair fern could damage spleen, so the herb should not be used in susceptible patients (7).

In modern medicine, 1.5 g of powdered drug is used as tea bag daily (3). According to ITM, in the form of decoction 20 g of the fronds is accepted (7).

Commercial products
In the form of topical solution, it is used as hair tonic three times daily. In addition, the plant is used in anti-dandruff shampoos and moisturizing creams.

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Many pharmacological effects including anti-diabetic, anti-obesity, anticonvulsant, analgesic, hypocholesterolemic, goitrogenic, anti-thyroidal, antibacterial, antifungal, wound healing, anti-hair loss, anti-asthmatic, anti-inflammatory, antidiarrheal and antispasmodic, antioxidant as well as diuretic, anti-urolithiasis, and detoxifying properties are ascribed to A. capillus-veneris. According to ITM, Maidenhair fern has been prescribed as single medicine or in poly, herbal formulations for the treatment of many diseases and among them respiratory and urogenital diseases were the most important one. The most used plants in combination with Maidenhair fern in traditional multi-herbal formulations have been revealed in Fig. 1, and among them liquorice, celery, fennel, sweet violet, Stavesacre, marshmallow, caltrop, and hyssop were the most cited plants.