THERAPEUTIC POTENTIAL OF HYPERICUM PERFORATUM: A REVIEW

THERAPEUTIC POTENTIAL OF HYPERICUM PERFORATUM: A REVIEW

Mansi Shrivastava^* and L. K. Dwivedi

Institute of Biomedical Sciences, Bundelkhand University, Jhansi-284128, UP, India

ABSTRACT: The irreversible effects of modern therapies and increasing drug resistance have augmented our reliance on medicinal plants for herbal remedy against the deadly and infectious diseases. Hypericum perforatum or St. John’s wort (SJW) family Clusiaceae has been used to treat depression, mental disorders, wounds, peptic ulcers, malaria, gout and arthritis. Various compounds of the plant are known as sedative, diuretic and expectorant according to their effects. The flowers and the aerial parts are commonly used in the preparations of traditional medicines. Hypericum perforatum with identified active compounds like Hypericins, Hyperforins is being studied for its anti-depressant activity in both humans and animals. It is also used in the treatment of pulmonary complaints, bladder troubles in suppression of urine, dysentery, worms, diarrhoea, hysteria and other haemorrhages and jaundice. Most of its therapeutic effects with mechanism of action are critically reviewed in the present paper

Hypericum perforatum, St. John’s wort, Anti-depressant agent, Hypericins, Hyperforins

INTRODUCTION: The Genus Hypericum L. (Guttiferae/Clusiaceae/Hypericaceae) containing 465 species globally ^{41, 48, 49} is a large family of plants with potential medicinal value. However, H. perforatum is mainly studied for its bioactivities due to its popularity among the depression patients. Hypericum perforatum commonly known as St. John’s wort is named so because of the traditional collection of its flower at the feast of St. John the Baptist on June 24^{th 48}. It is a perennial herb native to Asia and Europe ^{4, 38} but known globally for its traditional and modern uses. The use of this species as an herbal remedy to treat a variety of internal and external ailments dates back to the time of the ancient Greeks.

Since then, it has remained a popular treatment for anxiety, infection, and wound healing ^{38, 56, 57}. In last couple of decades, the majority of research on H. perforatum was based on its use as anti-depressant, which has expanded its popularity and made it among the top selling dietary supplements in the market ^{4, 14}.  Pharmaceutical companies, particularly in Europe, prepare standard formulations of this herb that are taken by millions of people. Moreover, it has also attracted the scientists’ brain for its anti-inflammatory and anti-microbial properties against the inflammatory diseases ^{14, 24}.

Recent research suggests the effectiveness of this herb in treating other ailments including cancer, inflammation related disorders, and bacterial and viral diseases, and used as an antioxidant and neuro-protective agent. Of the total 400 species, distributed in the temperate regions of the world, about 25 species are found in the Indian Himalayan Region (IHR). Amongst the species, Hypericum perforatum, grows in Himalayas at higher altitudes and in the central parts of the country, is a prospective herb to be used as a anti-depressant, anti-cancer, anti-tumour and anti-viral agent. Considering its anti-viral property, the plant is widely studied for its effect against the HIV species. Some biologically active constituents like hyperforin and adhyperforin (phloroglucinols), hypericin and pseudohypericin (naphthodianthrones), flavonoids, xanthones, oligomeric procyanidines, and amino acids have been detected in Hypericum ^{4, 38}.

Botanical Description:

The genus name Hypericum is derived from the Greek words hyper (above) and eikon (picture), in reference to the plant's traditional use in warding off evil by hanging plants over a religious icon in the house during St John's day (24^th June). The species name perforatum refers to the presence of small oil glands in the leaves that look like windows, which can be seen when they are held against the light ³³. Hypericum consists of herbs and shrubs having yellow or coppery flowers with four to five petals, numerous stamens, and a single pistil ¹⁰ and free branching typically range from 40 to 80 cm in height^{16, 36}. The stems and branches are densely covered by oblong, smooth margined leaves that range from 1 to 3 cm long and 0.3-1.0 cm wide. The leaves are interrupted by minute translucent spots that are evident when held up to the light. The upper portions of mature plants can produce several dozen five petaled yellow flowers that are typically 1.0-2.0 cm wide. The edges of the petals are usually covered with black dots. Crushed flowers produce a blood red pigment. By late summer, the flowers produce capsules that contain dozens of tiny, dark brown seeds. It thrives in poor soils, and is commonly found in meadows, fields, waste areas, roadsides, and abandoned mines and quarries ^{16, 27, 36}. Due to concerns over phototoxicity to livestock, H. perforatum is listed as a noxious weed in seven western states in the United States. Programs promoting its eradication are underway in Canada, California, and Australia.

Chemical Constituents:

Chemical investigations have detected seven groups of medicinally active compounds in H. Perforatum ³⁸. They include naphthodianthrones, phloroglucinols, and flavonoids (such as phenylpropanes, flavonol glycosides, and biflavones), as well as essential oils ^{2, 4, 11, 46}. There two major active constituents have been identified: hypericin (a naphtodianthrone) and hyperforin (a phloroglucinol).

Naphthodianthrones:

The class of compounds isolated from H. perforatum and the one which is the most researched naphthodianthrones ^{17, 18, 47}. They include hypericin, pseudohypericin, isophypericin, and protohypericin ^{2, 11}. Of these, hypericin—an anthraquinone derived pigment that is responsible for the red color of SJW oils. Hypericin is found in the flowers in the form of black dots that are located along the petals. Due to its chemical structure, hypericin is highly photoreactive.

Flavonoids:

Flavonoids in SJW range from 7% in stems to 12% in flowers ¹¹ and leaves ¹⁸. Flavonoids include flavonols (kaempferol, quercetin), flavones (luteolin), glycosides (hyperside, isoquercitrin, and rutin), biflavones (biapigenin), amentoflavone, myricetin, hyperin, oligomeric proanthocyanadins, and miquelianin, all of which are biogenetically related ^{2, 47}.

Lipophilic compounds:

Extracts of SJW contain several classes of lipophilic compounds with demonstrated therapeutic value, including phloroglucinol derivatives and oils. Hyperforin, isolated in concentrations of 24.5% ^{8, 47}, is a prenylated phloroglucinol. Hyperforin is unstable in the presence of both light and oxygen ²³. Other phloroglucinols include adhyperforin (0.2%1.9%), furohyperforin, and other hyperforin analogs ^{2, 11, 18, 21}. Essential oils are found in concentrations ranging from 0.05% to 0.9% ²¹. They consist mainly of mono and sesquiterpenes, specifically 2- methyloctane, nonane, α and β pinene, α terpineol, geranil, and trace amounts of myrecene, limonene, and caryophyllene ^{21, 46}.

Additional compounds:

These include tannins (ranging from 3% to 16%), xanthones (1.28 mg/100g), phenolic compounds (caffeic acid, chlorogenic acid, and pcoumaric acid), and hyperfolin. Additional compounds include acids (nicotinic, myristic, palmitic, and stearic), carotenoids, choline, pectin, hydrocarbons, and long chain alcohols ¹¹.

Pharmacological activities:

Anti-depressant:

St. John's wort (Hypericum perforatum L.) has been used for centuries to treat a number of common ailments (such as neuralgia, sleep disorders, wound healing, and hemorrhoids), but it is best known for its use in the treatment of mild to moderate depression ³⁹.

Responsible Compounds:

SJW is known to have several active ingredients including cyclopseudohypericin, hypericin, hyperforin, isohypericin, protohypericin, pseudohypericin and several other flavonoids ^{5, 13}. Each of these active components appears to have differing levels of contribution to its anti-depressant properties ⁵.

Mechanism of action: One of the proposed mechanisms of St. John's wort in the treatment of depression is the inhibition of the uptake of serotonin (5HT), dopamine (DA) and norepinephrine (NE) from the synaptic cleft of interconnecting neurons ^{8, 40}. A second contributing mechanism is the ability to bind to the major neuro-inhibitory receptor, gamma amino butyric acid (GABA A and GABA B) receptors, to block the binding of GABA^{3, 54}. This reduction in GABA ligand binding results in decreased central nervous system (CNS) depression. A third mechanism is an increase in the number or density of 5HT2 receptors in the frontal cortex of the brain, which is potentially beneficial when treating depression ³⁷.

A fourth and possibly fifth separate contributing mechanism is St. John's wort ability to inhibit the activity of both monoamine oxidase (MAO) and catechol O-methyl transferase (COMT) enzymes ^{37, 55}. Active form of both of these CNS enzymes metabolize dopamine precursors into inactive products and allows dopamine to metabolize to norepinephrine (NE) in the brain. Thus, inhibition of these enzymes in the CNS favors the metabolism of Dopamine and the formation of NE (Fig.1).

FIG.1: ANTI-DEPRESSIVE MECHANISM OF ST. JOHN’S WORT EXTRACT (SJW).

Anti-bacterial and anti-viral:

Extracts of H. perforatum have been used to treat cuts, abrasions, and other wounds for thousands of years. It is useful in reducing inflammation and is well known for its ability to serve as an antibacterial agent. Hyperforin, the main antibacterial component was determined to inhibit the growth of certain types of microorganisms especially for all Gram positive bacteria. However, no growth inhibitory effects were seen in the Gram negative bacteria ⁶. The SJW extracts have long been regarded as being effective against various classes of viruses. Flavonoid and catechin containing fractions of SJW are active against influenza virus ³⁴. Hypericin inactivates enveloped viruses at different points in their life cycle ²⁸, and their fusion with cell membranes ^{10, 28}. Considering to that Hypericin is used as natural candidate to inactivate several enveloped viruses present in human blood and also to treat Acquired Immunodeficiency Syndrome (AIDS) patients ^{22, 33}. Other reverse-transcribed viruses like hepatitis virus B and C (HBV and HCV) have been found to be inhibited by hypericin in vitro ^{37, 55}. It was found hypericin ineffective against the hepatitis C virus in a doses study ²⁵.

Some recent reports showed that isoquercetrin in H. perforatum extract could inhibit H1N1 influenza virus replication in MDCK cells. However, most observations of anti-viral activity of Hypericum were acquired from in vitro studies and a limited number of animal studies, while human clinical trials often showed little or no significant effect. Studies on other viruses have shown the hypericin induced in-vitro inactivation of Bovine Diarrhea Virus (BVDV) in the presence of light ⁴³.

Anti HIV Property:

Hypericin induces changes in p24 protein and the p24 containing gag precursor, p55 and the formation of an anti p24 immuno-reactive material which inhibit the release of reverse transcriptase activity ¹⁰. However, in a phase I clinical trial, it was found that hypericin had no beneficial effect on administration to 30 HIV infected patients with CD4 counts less than 350 cells/mm^{3 20}. Recently, in a study, 3- hydroxy lauric acid was found in the field grown H. perforatum which has shown better anti HIV activity ⁴³.

Mechanism of action:

With no apparent effect on viral nucleotide, transcription and translation being observed, the authors speculated that the anti-viral mechanism of the Hypericum was having a direct interference with virus infection and shedding, or inactivation of virus, or disruption of lipid membrane of virus. However, conclusive clinical evidence has yet to be found to support the in vivo efficacy of hypericin and H. perforatum against HIV.

The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway are responsible for transmitting signals from a myriad of cytokine and hormone receptors ⁴⁵.  Negative regulation of the JAK/STAT pathway is carried out through suppressor of cytokine signaling (SOCS) proteins, whose transcription is controlled by STATs ⁴⁴.  Although SOCSs are important to contain inflammation, which are manipulated by pathogens such as influenza virus by regulating SOCS3 expression but there are certain biological components found in H. perforatum extract which may inhibit the viral infection.

Anticancer:

Hyperforin and hypericin have also been examined for their anticancer properties. Hyperforin inhibits tumor cell growth in vitro ⁵¹. Studies demonstrated that hyperforin in conjunction with polyphenolic procyanidin B2 effectively inhibited the growth of leukemia in K562 and U937 cells, brain glioblastoma cells LN229, and normal human astrocytes ²³. Hypericin also inhibits the growth of cells derived from a variety of neoplastic tissues, including glioma, neuroblastoma, adenoma, mesothelioma, melanoma, carcinoma, sarcoma, and leukemia¹⁵. Hypericin being photodynamic compound within photoactivated with white light or ultraviolet light or both could induce nearly complete apoptosis (94%) in malignant cutaneous T cells and lymphoma T cells ¹⁵. Exposing tumors cells to hypericin in conjunction with laser irradiation led to toxic effects on human prostatic cancer cell lines ⁹, human urinary bladder carcinoma cells ²⁶, and pancreatic cancer cell lines ²⁹ in in-vitro systems.

As a matter of attention, hypericin alone has only a weak inhibitory effect on cancerous cell growth, whereas methanolic extract of SJW together with hypericin leads to long lasting inhibition of cell growth, induces apoptosis, and decreases phototoxicity ^{50, 52}. Considering the encouraging results of hyperforin and hypericin as anticancer agents, more research is needed to evaluate their efficacy, mode of action, and adverse interactions.

Mechanism of action: The mechanism involves induction of apoptosis (programmed cell death) through the activation of caspases, which are cysteine proteases that trigger a cascade of proteolytic cleavage in mammalian cells. Hypericin with its greater photodynamic properties¹ acts as a powerful natural photosensitizer in the presence of oxygen and light. It generates superoxide radicals that form peroxide or hydroxyl radicals, or singlet oxygen molecules that kill tumor cells. Hence, in future, hypericin can be used as a component of photodynamic therapy (PDT).

 Neuroprotective:

35. H. perforatum serves as a neuroprotective agent against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease in mice ³⁵. H. perforatum extract led to the inhibition of MAOB (monoamine oxidase B) activity and decreased astrocyte activation in striatal area of (MPTP) induced mice. The flavonols quercetin and kaempferol provide neuroprotective action by decreasing oxidation of the mitochondrial lipid membrane and maintaining mitochondrial transmembrane electric potential ⁵³. They lower the ability of mitochondria to absorb calcium. Extracts of SJW protect against cell death caused by amyloid P peptides (Abeta) that form plaques in the brains of those suffering from Alzheimer's disease. Hypericin may interfere with the processes of polymerization of the beta-amyloid peptide responsible for the onset of Alzheimer’s diseas ¹⁹.

Other Activities:

12. H. perforatum shows promise as an anti-inflammatory agent. Rats fed doses of SJW showed decreased levels of blood and bowel enzymes associated with colonic inflammation ¹², and had lower incidences of gastric ulcers ¹².

The extracts of H. perforatum decrease oxidative stress and consequently prevent neurotoxicity, inflammation, and gastrointestinal problems. H. perforatum extract has been used over thousands of years as a wound healing agent. The chicken embryonic fibroblasts exposed to SJW extract enhanced collagen production, followed by the polygonal shape activation of fibroblast cells that is responsible for wound closure ⁴².

Future Perspectives:

In recent years, many studies have proven the efficacy of some HP extracts in the treatment of depression, bacterial and viral infection, neurological disorders, etc. It has also received special attention due to its pharmacological properties, including antiseptic, spasmolytic, tonic, diuretic and anesthetic remedies. Despite the dozens of clinical, in vivo, and in vitro studies conducted on the medicinal attributes of SJW, several unanswered questions still prevail regarding its therapeutic value, mechanisms of action, and adverse interactions. The future research must focus on resolving the apparent contradictions related to this herbal plant. Additional research is needed regarding the therapeutic value of SJW as anti-cancerous, anti-HIV, immuno-modulatory agent and so on. Moreover, the potency of hypericin, hyperforin, and flavonoids must be further elucidated.

Anti-bacterial property of SJW is reported against the Gram positive bacteria but it is still to be thoroughly studied against the Gram negative bacteria. Hypericin was tested as anti-HIV drug, but some more studies are required to understand its mechanism of action and efficacy in serious AIDS patients. The anti-retroviral activity of 3-hydroxy lauric acid reported to be found in the field grown SJW extract may further be studied for its in-vivo effects. As anti-cancer agent evaluation of efficacy, mode of action and adverse effects of hypericin and hyperforin is needed.

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    Shrivastava M and Dwivedi LK: Therapeutic Potential of Hypericum Perforatum: A Review. Int J Pharm Sci Res 2015; 6(12): 4982-88.doi: 10.13040/IJPSR.0975-8232.6(12).4982-88.

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