THE SUCCESS STORY OF ST. JOHN'S WORT

Dr. Vikas KumarAssociate Professor of PharmacologyDepartment of PharmaceuticsIIT (BHU), Varanasi

INTRODUCTION Hypericum perforatum is a flowering

plant in the family Hypericaceae It is well known as St. John’s Wort because

its flowers bloom around St. John’s Day and Wort is an Old English term for “Herb”

It is also a Myth that, the red pigments which are exuded from buds and flowers were associated with the blood of St. John the Baptist 2

St John's Wort  is native to Europe and Asia It is a herbaceous perennial herb and can

grow to 1 m high Flowers are bright yellow in colour with

conspicuous black dots and measure up to 2.5 cm across

The leaves are yellow-green in colour, with conspicuous translucent dots, giving them a 'perforated' appearance

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Hypericum perforatum was known since Greek and Roman times

In Medieval Europe, the herb was used to treat emotional and nervous complications

In European folk medicine, St John's Wort was also used as an antiphlogistic to treat bronchial and urogenital tract inflammations, hemorrhoids, traumas, burns, scalds and ulcers 4

Hyperforin and hypericin were the very first bioactive secondary metabolites of this plant

Other reported bioactive metabolites are

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CHEMICAL CONSTITUENTS OF ST. JOHN’S WORT

In 1935, very first report was published on the efficacy of St. John’s Wort (SJW) against depression

Much earlier than the discovery of synthetic tri-cyclic antidepressants

The main therapeutic focus of SJW research has been its CNS modulating properties

However, major interest in the use of SJW for treatment of CNS disorders starts after 1980s in Germany 6

PRECLINICAL STUDIES OF ST. JOHN’S WORT

In various animal models, SJW has shown: Antidepressant Anxiolytic Anti-stress Anti-aggressive Anti-inflammatory and analgesic Anti-diabetic, hypolipidemic and anti-obesity like

activity Beneficial effects in neurological disorders

associated with diabetes 7

Repeated daily oral administration Indian Hypericum perforatum (IHp) decreased

immobility time in rat behavioural despair model

In rat learned helplessness test, IHp shows significant reduction in number of escape failures as compared to vehicle control group

Observations from our laboratory have revealed that, IHp shows significant antidepressant activity after repeated daily oral administration(Kumar et al, IJEB, 1999, 37: 1171-1176) 8

ANTI-DEPRESSANT & ANXIOLYTIC ACTIVITY OF SJW

Figure 1: Effect of IHp on antidepressant activities in rats. *p<0.05 vs. vehicle

Earlier, hypericin was thought to be an active constituent responsible for the antidepressant activity of SJW

Later, hyperforin, has been projected as primarily responsible for the antidepressant activity of SJW

Hyperforin shows its antidepressant activity by inhibiting the neuronal re-uptake of several biogenic amines and amino acid neurotransmitters (Serotonin, Dopamine and Noradrenaline)

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(Chatterjee et al., Life Sci, 1998, 63: 499-510)

In our laboratory, we have evaluated SJW for its anti-anxiety activity in different animal models

SJW dose dependently (100 and 200 mg/kg) increases the open field ambulation, rearings and self grooming in rat open field exploratatory behaviour test

SJW (100 and 200 mg/kg) significantly increased the number of open arms entries and the time spent in the open arms in both elevated plus maze and elevated zero maze behavioural tests

(Kumar et al., IJEB, 2000, 38: 36-41)10

Hypericum perforatum extract (HpE) was well active against diabetes associated depression

HpE treatment dose dependently (100 and 200 mg/kg) reduced the immobility period in despair forced swim test in diabetic rats

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SJW AGAINST DIABETES ASSOCIATED DEPRESSION

Figure 2: Effect of HpE in forced swim test in rats. *p<0.05 vs. normal control; $ p<0.05 vs. diabetic control

(Husain et al., Acta Pol Pharm, 2011, 68: 913-918)

In open-field exploration test, diabetic rats treated with HpE (100 and 200 mg/kg) showed significant increase in self grooming and rearing compared to vehicle treated diabetic control rats

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SJW AGAINST DIABETES ASSOCIATED ANXIETY

Figure 3: Effect of HpE in open-field exploration test in rats. *p<0.05 vs. normal control; $ p<0.05 vs. diabetic control

(Husain et al., Acta Pol Pharm, 2011, 68: 913-918)

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In Elevated plus-maze test, diabetic rats treated with HpE (100 and 200 mg/kg) significantly increased the number of open arms entries and the time spent in the open arms compared to vehicle treated diabetic control rats

Figure 4: Effect of HpE in elevated plus-maze test in rats. *p<0.05 vs. normal control; $ p<0.05 vs. diabetic control

(Husain et al., Acta Pol Pharm, 2011, 68: 913-918)

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MECHANISM OF ANTIDEPRESSANT ACTION

SJW increases the level of the biogenic

neurotransmitters (Norepinephrine and 5-hydroxy

tryptamine) in brain by blocking their neuronal uptake

It was also reported that SJW preferentially increases

extracellular dopamine levels in the rat prefrontal cortex

by inhibiting monoamine oxidase

(Kumar et al., IJEB, 2001, 39: 334-338; Husain et al., Acta Pol Pharm, 2011, 68: 913-918)

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MECHANISM OF ANXIOLYTIC ACTION SJW facilitated GABAergic neurotransmission in brain

through inhibition of neuronal reuptake of GABA

(Kumar et al, IJEB, 2002, 38: 36-41)

SJW extract when tested in memory retrieval training on a one-trial passive avoidance task in mice increased the step-down latency periods

It was also reported that, repeated daily administration of SJW extract significantly increased the step-through latency periods on electroconvulsive shock induced amnesia in rats

Observations reported also revealed that, hyperforin significantly retrieved the loss of memory when tested on scopolamine-induced amnesia in rats

NOOTROPIC ACTIVITY OF SJW

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(Kumar et al., Phytother Res, 2002, 16: 210-216; Khalifa, J Ethnopharmacol, 2001, 76: 49-57)

Downregulation of the dopamine D2 receptor and upregulation of serotonin 5-HT2A and benzodiazepine receptors in brain have facilitated the effect of SJW extract on retrieval of memory

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MECHANISM OF NOOTROPIC ACTION

(Kumar et al., Phytother Res, 2002, 16: 210-216; Khalifa, J Ethnopharmacol, 2001, 76: 49-57)

Repeated daily administration of Indian Hypericum

perforatum (IHp) significantly suppressed chronic stress induced gastric ulceration in rats

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ANTI-STRESS ACTIVITY OF ST. JOHN’S WORT

Figure 5: Effect of IHp in stress induced gastric ulceration in rats. *p<0.05 vs. stress control

(Kumar et al, IJEB, 2001, 39: 344-349)

Hypericum perforatum is a potent adptogen It was reported that, SJW shown its anti-stress activity by

decreasing the plasma cortisol level during stress

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MECHANISM OF ANTI-STRESS ACTIVITY

(Kumar et al, IJEB, 2001, 39: 344-349; Mozaffari et al., Pharmacog Mag, 2011, 7: 213-223)

Indian Hypericum perforatum extract (IHpE) was investigated for its anti-aggressive activity in foot shock-induced aggression test and isolation-induced aggression test in mice

Observations reported from our laboratory was revealed that, repeated daily administration of IHpE significantly suppressed the aggressive behaviour as compared to vehicle treated control group

It was also reported that, IHpE shown its anti-aggressive activity by inhibiting neuronal reuptake of neurotransmitters in brain

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ANTI-AGGRESSIVE ACTIVITY OF ST. JOHN’S WORT

(Husain et al, Pharmacologyonline, 2009, 1: 432-444; Kumar et al., Drug Discov Ther, 2009, 3: 162-167)

Effect of IHp was investigated on nicotinamide streptozotocin induced diabetic rats

Repeated daily treatment with IHp significantly reduced the elevated blood glucose level

IHp sensitized the insulin receptors and glucose trasporters

ANTIDIABETIC ACTIVITY OF ST. JOHN’S WORT

22Antidiabetic action

(Husain et al, Drug Discov Ther, 2009, 3(5): 215-220; Husain et al, Drug Res, 2011; 68: 913-918)

Figure 6: Effect of IHp on fasting blood glucose level of diabetic rats. *p<0.05 vs. normal; $p<0.05 vs diabetic

Observation from our laboratory revealed that SJW significantly inhibited inflammation on:

Carrageenan induced pedal edema in rats Cotton pellet induced granuloma in rats SJW extract also showed significant analgesic activity on: Tail flick latent period in rats Hot plate reaction time in mice SJW showed its anti-inflammatory and analgesic activity

by inhibiting the production of prostaglandin by blocking COX enzymes

ANTI-INFLAMMATORY & ANALGESIC ACTIVITY OF SJW

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(Kumar et al., IJEB, 2001, 39: 339-343)

Since the 1980s, numerous clinical trials have been conducted on Hypericum for the treatment of varying types and degrees of depression

Linde and Associates, in 1996 performed meta-analysis-clinical studies of SJW extract (900 mg/day)

CLINICAL STUDIES OF ST. JOHN’S WORT

23 randomized trials 1757 outpatients with depression

4-6 weeks duration

SJW significantly superior to placebo and similarly effective as standard antidepressants while producing fewer side effects

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(Linde et al., BMJ, 1996, 313: 253-258)

In 2000, at seven German medical clinics, Schrader conducted a double blind study for 6 weeks period

Out of 240 patients, 114 were given SJW extract (600 mg) and 126 patients with Prozac (Fluoxetine)

While the two medications showed similar efficacy, but Prozac reported more side effects (gastric irritation, vomiting, erectile dysfunction) than SJW

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(Klemow et al, Herbal Med, 2011, 11)

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MARKETED PRODUCTS OF ST. JOHN’S WORT

S N Products Indication(s) Company

1Nervous tension

and mild anxiety

Blackmores Ltd. New South Wales, Australia

2Depression,

anxiety and low mood

Swisse Vitamins Pvt Ltd.Collingwood, Australia

3Mild depression and low mood

Schwabe Pharma (UK) Ltd.Marlow, UK

4Nervous tension

and anxiety Fushi Wellbeing Ltd.

London, UK 26

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S N Products Indication(s) Company

5

Headache, Nerve pain, depression, inflammation and

wound healing

Camp Wander (UK) Ltd.Marlow, UK

6Low mood and mild anxiety

 Lamberts Healthcare Ltd.Tunbridge Wells, UK

7Low mood and

anxiety

A.Vogel Herbal RemediesBioforce (UK) Ltd.

Irvine, UK

8Low mood and

anxietyOnly Natural Inc.New York, USA 27

S N ProductsIndication(s

)Company

9Nervous

tension and mild anxiety

East West Tea Company, LLC.Oregon, USA

10Low mood and mild anxiety

 Indian Herbs Specialties Pvt Ltd. Saharanpur, India

11Analgesic

and wound healing

Weleda Ltd.Arlesheim, Switzerland

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Several pharmaceutical-grade preparations of SJW are currently valued for treating depression and other mood disorders

SJW is reputed as one of the best-selling herbs of the last decade

Commercially, SJW is available in the form of tablets, capsules, dried powders and tinctures

In the United States, SJW, like all herbal remedies, is listed as a dietary supplement by the Food and Drug Administration (FDA) 29

MARKET POTENTIAL OF ST. JOHN’S WORT

With an estimated US$315 million turnover, Europe holds the 1st position worldwide

In the United States, annual sales reached a peak of US$315 million in 1998, but declined to approximately US$60 million by 2006

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(Klemow et al, Herbal Med, 2011, 11)

Over the past 20 years, SJW has become a mainstream alternative treatment for depression

Thanks to its popularity, the effectiveness of SJW has been intensively studied since the mid-1980s

It is interesting to note that the greatest clinical success for the SJW was achieved in Europe

SJW does appear to be an effective treatment for other disorders, particularly some skin ailments, inflammation and certain forms of cancer

Therefore, drug discovery projects based on SJW should not be limited to hyperforin and also should not be limited to antidepressant activity

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AND THE STORY GOES ON…

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ACKNOWLEDGEMENTS