A REVIEW ON THE PHYTOPHARMACOLOGICAL PROPERTIES, UNANI AND MODERN PHARMACOLOGY OF BISFAYEJ ( POLYPODIUM VULGARE LINN)

Different herbs and their constituents are used for medicinal purposes by approximately 80 percent of the world population, which is evidenced by the rapidly growing global and national markets of herbal drugs. This review is aimed at presenting an overview of the medicinal properties of P. vulgare , its phytoconstituents and diverse pharmacological activities. To retrieve the information related to this drug, a thorough literature survey was undertaken using the various classical Unani and Herbal literature books viz., Al-Qānūn fi’l Tibb, Makhzan al - Mufradat, Kanzul Advia Mufradah, Ilmul Adwiya Nafisi, Taj al-Mufradat, Indian Materia Medica, Indian Medicinal Plants among others. Further , for other traditional uses, phytoconstituents, pharmacological activities and research studies of the drug, various online bibliographic databases like Pub Med, Google Scholar, Science Direct, Web of Science and Scopus were meticulously searched. The keywords used for the search included “ Polypodium vulgare ”, “ Bisfayej ”, “ Polypody root and rhizome”, “Phytoconstituents of Polypodium vulgare ”. P vulgare is proven to possess neuro-psycho-pharmacological, CNS depressant and anti-epileptic activity through its anti-cholinesterase and 5-hydroxytryptamine (5-HT) stimulatory effect. Various clinical researches validate the use of P vulgare in the management of conditions such as Epilepsy, Arthritis, Leprosy, Melancholy and Alzheimer’s disease. Further studies are needed to unravel its other pharmacological activities.


INTRODUCTION
Polypodium vulgare Linn is a small, wintergreen, perennial fern that belongs to the Polypodiaceae family [1].It is one of the most widely distributed fern species in the world [2].The Latin name Polypodium derived from the word poly (many) and podos (feet) has arisen from the particular shape of its rhizomes, branching like feet [1].The plant usually ranges from 10 to 30 cm in height, having a scaly stem.The stem scales are variable in size, usually 4 mm long, narrowly triangular, and red-brown colour [3].It has slender knotty rhizomes and curving fronds that are dotted with brown spores on the lower surface.The rhizome is fibrous, having a dark brownish color on the outside and greenish color within [4][5][6][7].It is covered with cavernous suckers like those on the arms of the polypus or centipede [4,5,7].

A record of the medicinal applications of Polypodium vulgare in the primitive period
Polypodium vulgare has been used for its various properties since the ancient Greek era [8].The medicinal and therapeutic uses of the drug are thoroughly documented in old classical texts.The renowned Greek philosopher Dioscorides, in his classical texts from 1 st century AD has opined the purgative properties of the polypody root and mentioned its use to purge phlegm.He also stated its use as an ingredient of a plaster applied to dislocated fingers and to sores that occurred between the fingers [9].The thick stems were earlier used as a remedy for diseases of the air passages, such as cough, cold, adenoids and multiple other purposes [5,10].Its tea or decoction was used by the Indians for the treatment of pleurisy, hives, stomachache and inflammations.According to an ancient source in Telemark, Norway, it is believed that P. vulgare grew for the first time at a rock cleft where Virgin Mary squirted some of her breast milk.Hence, in folk medicine, the name "Mariebregne" (Mary fern) is used for this drug [1].Its rhizome was also used as a sweetener.It is considered as an important drug for liver ailments, pleurisy and intestinal worms [1].

Habitat
Polypodium vulgare Linn is native to Europe, Africa and Eastern Asia, mostly in northern or upland areas [10,11].It is a common specie found throughout Scandinavia [10].The plant grows to a maximum during the months of October and November.It has only one branch with small leaves and does not bear any flowers [4,5,12].It can grow to an average height of 30 cm and is well tolerant to successive dry periods [8].This fern is often encouraged to grow as a garden plant but does not acclimatize easily [13].In India, the root of Bisfayej is procured from other countries [7,11].

General description of the drug in the classical Unani texts
Bisfayej is known by various names in different parts of the world, "Azrasul Kalb" "dog's tooth," in allusion to the toothed appearance of the leaves, "Kathirul Arjil" "many-footed," and "Thakibul Hajar" "penetrating stones" [7,14].
On the basis of its geographical location and traditions, it has different therapeutic applications in different regions.The rhizome having fibrous projections and appearing grassy green or dark brown in colour is used as a drug.It has been observed that the fresh root, which is grassy green in colour becomes darker when kept for a long period [5,6].The grassy green fresh root is considered best for medicinal purposes [6,7].Polypody root is used both fresh and dried, however, the leaves are also sometimes used for its medicinal value [15].The rhizome of the size of the little finger, that appears fresh and having taste like cloves is considered of best quality [5,6,16].The surface is hard, hairy, rugous and longitudinally fissured.The upper surface presents several horn-like tubercles or scaly projections of suckers.Each projection is curved, 0.5 inches long and fissured.Due to these projections the drug is named as "Kathirul Arjil" resembling the legs of a centipede [4,6,8].Regarding the temperament (Mizaj) of P. vulgare Linn., different authors have different opinions.Most of the Unani physicians are of the view that it is hot in the second degree [7,11,12,16,17] and dry in the third-degree [12].

Ethnobotanical description
P. vulgare is a small, terrestrial or epiphytic fern that grows into large colonies, with a creeping, densely hairy or scaly rhizome bearing fronds at intervals along its length.The fern is rather thick, creeping and ramifying, having scaly stems and long stalk, usually 10-30 cm.The stem scales are narrowly triangular, red-brown in colour, variable in size, usually up to 4 mm long [10].The dried rhizome is flattened to round in cross-section and yellowish-brown to dirty brown externally and slightly lighter at the cut ends.The drug is characterized by a ferry odour, sweet, astringent and nauseous taste and moderately hard and brittle in fracture [11].It has long, glabrous, dull green, deeply pinnatifid leaves having various crests arranged alternately in 2 rows.The leaves and petioles are above the ground.The pinnae have entire or crinate margins, more deeply serrate.The veinlets usually divide 2-3 times [6,10,11].It has brown, brownish-yellow to rusty brown sori in two rows on the dorsal side, on each side of the midrib, mainly in the upper half of the blade [10].
According to an assessment report on Polypodium vulgare L (2008), the more accurate description of the P. vulgare part used medicinally should be rhizome and not root.It states that "a rhizome is typically a horizontally oriented underground stem that may outwardly appear root-like but has definite nodes and internodes" [1].
Under a microscope, the transverse section of the rhizome is somewhat oval to round in shape.The rhizome is seen to consist of a delicate cellular structure containing much starch and green granular matter.It is traversed by large bundles of scalariform vessels [11].

Phytoconstituents of P. vulgare and their possible mechanism of action
Important groups of phytochemicals that have been isolated from P. vulgare are alkaloids, tannins, flavonoids and phenolic compounds [18].20-hydroxyecdysone is the most abundant ecdysteroid isolated from the rhizomes.Minor amounts of other phytoecdysteroids, such as polypodine B (5,20E) and the parent ecdysone (E) have also been found.However, variability in its contents has been reported as a possible influence of microclimate due to geographic location as well as the season of collection.Part of the plant examined and the age of the field-collected material is also said to give rise to such differences [2,19].

Pharmacological actions and therapeutic implications of P. vulgare
The traditional use of polypody rhizome has been documented in several handbooks and in the scientific literature.

Dafi'-i-Qulanj (antispasmodic)
P vulgare has been used as an antispasmodic agent and has been found effective in various types of colics.Along with some other drugs like Anisoon (Aniseed) and Multi (Liquorice) [16], it is useful in cough and Dama (asthma) as it relieves bronchospasm [5,16].

Dafi'-i-Tashannuj (anti-convulsant)
The drug has been found to be effective in epileptic disorders along with Amaltas (Cassia fistula L).

Hazim (digestive)
It assists in the digestive processes and helps in the digestion of milk, causing first its precipitation and later followed by its dissolution and purges out phlegm from the stomach [5,6,16,25].

Analgesic activity
The aqueous extract of Polypodium vulgare was found to possess analgesic activity by increasing the reaction time in rat's postadministration [27].

Antimicrobial activity
The methanol extract of P vulgare was screened for antimicrobial activity by measuring the minimum bacterial concentration (MBC) and minimum inhibitory concentration (MIC) values against the gram-negative and gram-positive bacteria named Staphylococcus aureus and Escherichia coli by standard assay.It is indicated that P vulgare ferns have the highest antibacterial activity and it is the most suitable source for the discovery of antibiotic drug [28].

Antioxidant property
The phenolic compounds present in rhizome have antioxidant properties and also have a protective chemical barrier against environmental stresses [26].

Cholinesterase inhibitory activity
The rhizome of Polypodium vulgare Linn.was evaluated for its cholinesterase inhibitory activity and has been recommended for the treatment of Alzheimer's disease symptoms [29].

CNS depressant and anti-epileptic activity
The rhizome of P. vulgare has been found to possess a protective effect in drug-induced catalepsy in swiss mice, thus suggesting that it enhances the transmission of dopamine in CNS and possibly acts as a D2 receptor agonist.Hence, it can be explored for various psychoneurological disorders [30].The rhizome extract was found to possess CNS depressant and anti-epileptic activity [27].
Ma'jun Najah and its two developed dosage forms, hydro-alcoholic extract and sugar-free granules in mice were found to have anticonvulsant activity, thereby possessing a protective role against epilepsy [31].

Effect on 5-hydroxytryptamine (Serotonin-5HT)
Authors of the study on Sharbate-Ahmed Shah (SAS), discussed that this compound formulation (containing Bisfayej) increased the availability of tryptophan in blood and brain and hence increases 5hydroxytryptamine (Serotonin: 5HT) in the brain.It was concluded that SAS contains some active principles which increase the availability of neurochemicals (tryptophan and 5HT) and decrease the 5HT turnover rate thus causes antidepressant and anxiolytic effects in experimental animals [32].

Hypotensive effect
Aqueous extract of the roots of P. vulgare (PV) produced CNS depressant effect.It decreased the spontaneous motor activity, prolonged the pentobarbitone-induced hypnosis, reduced body temperature and increased the reaction time to pain stimuli.In anesthetized dogs, the Polypodium vulgare extract at low dose produced a fall in blood pressure and which in short duration is rapid at the onset.However, with a high dose, there was a rise in blood pressure and then it suddenly fell down due to βadrenoceptor agonist activity and vasodilation.Polypodium vulgare showed the hypotensive effect that is caused due to catechins [27].

Neuro-psychopharmacological activity
The aqueous extract of the P vulgare linn showed neuropsychopharmacological activity.Its administration showed decreased alertness, mild passivity and decreased locomotor activity in mice and rats [30].

Smooth muscle relaxation effect
P. vulgare has a dual receptor block mechanism that arbitrates smooth muscle relaxation effect.A study demonstrated the uses of P vulgare in smooth muscle's contraction and also described its applications to in vivo and in vitro experimental techniques with its possible underlying mechanisms [33].The findings of the study revealed high antioxidant and antifungal capacities of flavonoids and tannins of P vulgare, but weak anti-inflammatory activities and affirmed harmful above 100 µg/ml [18] 2.
In vitro cholinesterase inhibitory activity of some plants used in Iranian traditional medicine.Saeedi M. 2017

Natural Product Research
The rhizome of Polypodium vulgare Linn.was evaluated for its cholinesterase inhibitory activity and has been recommended for the treatment of Alzheimer's disease symptom.
[29] Majoon Najah and its two developed dosage forms, hydroalcoholic extract and sugar-free granules in mice, were found to have anticonvulsant activity, there by possessing protective role against epilepsy.

Effect of rhizome extract of
[31]

Studies illustrating the adverse events
The polypody rhizome may cause a skin rash when applied externally [9].Also, it was found to cause a rash after its ingestion which was reportedly harmless.Nevertheless, it is not established by any scientific literature [35].A minor adverse reaction in form of a mild laxative effect is noted when polypody root is used as a traditional indication in cough and cold.Polypody rhizome is not recommended during pregnancy, breastfeeding and in children younger than 12 y of age due to lack of available scientific data [1].

Conclusion and future potential
The extensive survey of literature revealed that P. vulgare has been traditionally used worldwide since ancient times due to its diverse medicinal properties and pharmacological activities.The overall ethnobotanical, ethno-pharmacological and phytochemical studies of P vulgare L were well emphasized in this review article.Since time immemorial, it has played a significant role in the area of medicine and various clinical studies have confirmed that it has a wide application in the management of various diseases such as Epilepsy, Arthritis, Leprosy, Melancholy and Alzheimer's disease.However, further evaluation needs to be carried out in order to explore the concealed areas and its practical clinical applications, which can be used for the welfare of mankind.

ACKNOWLEDGMENT
Authors acknowledge the tremendous help obtained from the scholars whose articles are cited and included in references for this review article.