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"Article Title: Botanical Research Bulletin Vol.1, No. 6
The unique pharmacology of coleus forskohlii.
A plant used since antiquity in Hindu and Ayurvedic traditional medicine is the source of an amazing compound of unique biological importance. The plant, Coleus forskohlii, is the source of the compound forskolin. A large-scale screening of medicinal plants by the Indian Central Drug Research Institute in 1974 revealed the presence of a hypotensive and spasmolytic component of C. forskohlii which was named coleanol. Additional investigation determined the exact chemical structure of this labdane diterpene and the name was changed to forskolin.
Between 1981 and 1994 forskolin has been used in well over 5,000 in vitro research studies designed to better understand cellular processes governed by cAMP. While most of these studies have used this isolated constituent, there is evidence that other components within the potant extract enhance the absorption and biological activity of forskolin. The pharmacological activity of forskolin is, however, substantiating the traditional uses of C. forskohlii which includes such things as cardiovascular disease, abdominal colic, respiratory disorders, painful urination, insomnia, and convulsions.
Mechanisms of action
The basic mechanism of action of forskolin is the activation of an enzyme, adenylate cyclase, which increases cyclic adenosine monophosphate (cAMP) in cells. Cyclic AMP is perhaps the most important cell-regulating compound. Once formed it activates many other enzymes involved in diverse cellular functions. Under normal situations cAMP is formed when a stimulatory hormone (e.g., epinephrine) binds to a receptor site on the cell membrane and stimulates the activation of adenylate cyclase. This enzyme is incorporated into all cellular membranes and only the specificity of the receptor determines which hormone will activate it in a particular cell.
Forskolin appears to bypass this need for direct hormonal activation of adenylate cyclase via transmembrane activation. As a result of this activation of adenylate cyclase intracellular cAMP levels rise. The physiological and biochemical effects of a raised intracellular cAMP level include: inhibition of platelet activation and degranulation; inhibition of mast cell degranulation and histamine release; increased force of contraction of heart muscle; relaxation of the arteries and other smooth muscles; increased insulin secretion; increased thyroid function; and increased lipolysis. Recent studies have found forskolin to possess additional mechanisms of action independent of its ability to directly stimulate adenylate cyclase and cAMP dependent physiological responses.
Specifically forskolin has been shown to inhibit a number of membrane transport proteins and channel proteins through a mechanism that does not involve the production of cAMP. The result is again a transmembrane signaling that results in activation of other cellular enzymes. Research is underway in the attempt to determine the exact receptors to which the forskolin is binding. Another action of forskolin is on antagonizing the action of platelet-activating factor (PAF) by interfering with PAF binding to receptor sites. PAF plays a central role in many inflammatory and allergic processes including neutrophil activation, increasing vascular permeability, smooth muscles contraction including bronchoconstriction, and reduction in coronary blood flow.
After treatment of platelets with forskolin prior to PAF binding, a 30% to 40% decrease in PAF binding was observed. The decrease in PAF binding caused by forskolin was concomitant with a decrease in the physiological responses of platelets induced by PAF. However, this forskolin-induced decrease in PAF binding was not a consequence of cAMP formation as the addition of a cAMP analog could not mimic the action of forskolin. Additionally, the inactive analog of forskolin, dideoxyforskolin, which does not activate adenylyl cyclase, also reduced PAF binding was due to a direct effect of this molecule and its analog on the PAF receptor itself or to components of the post receptor signaling for PAF. The therapeutic ramifications of c. forskohlii based on the pharmacology of forskolin are immense. There are many conditions where a decreased intracellular cAMP level is thought to be a major factor in the development of the disease process. At present C. forskohlii appears to be extremely well indicated in these types of conditions which include: eczema (atopic dermatitis), asthma, psoriasis, angina, and hypertension. this review shall focus primarily on these relevant clinical applications.
Asthma and other allergic conditions
Allergic conditions such as asthma and eczema are characterized by a relative decrease in cAMP in the bronchial smooth muscle and skin respectively. As a result of this derangement, mast cells degranulate and smooth muscle cells contract. In addition, these allergic conditions are also characterized by excessive levels of PAF.
Current drug therapy for allergic conditions like asthma and eczema is largely designed to increase cAMP levels by using substances which either bind to receptors to stimulate adenylate cyclase (e.g., corticosteroids) or inhibit the enzyme phosphodiesterase which break down cAMP once it I formed (e.g., methyxanthines). These actions are different then forskolin's ability to increase the initial production of cAMP via a transmembrane activation of adenylate cyclase. The cAMP elevating action of forskolin supports the use of C. forskohlii extracts used alone or in combination with standard drug therapy in the treatment of virtually all allergic conditions. Coleus forskohlii extracts may be particularly useful in asthma as increasing cellular levels of cAMP results in relaxation of bronchial muscles and relief of symptoms in asthma.
Forskolin has been shown to have remarkable effects in relaxing constricted bronchial muscles in asthmatics. The bronchials are composed of what is known as smooth muscle. This type of muscle is also found in the gastrointestinal tract, uterus, bladder, and arteries. Forskolin has been shown to have tremendous antispasmodic action on these various smooth muscles. This antispasmodic action of forskolin supports the long time use of C. forskohlii in the treatment of not only asthma, but also intestinal colic, uterine cramps (menstrual cramps), painful urination, angina, and hypertension. Forskolin's ability to relax smooth muscle in bronchial asthma is most probably due to an increase in cAMP, although forskolin has other anti-allergic activities such as inhibiting the release of histamine and the synthesis of allergic compounds.
One double-blind clinical study sought to determine the antiasthmatic effects of forskolin compared to the drug fenoterol. Sixteen patients with asthma were given single inhalative doses of fenoterol dry powder capsules (0.4 mg), metered doses of fenoterol (0.4 mg) and forskolin dry powder capsules (10.0 mg). All substances caused a significant improvement in respiratory function and bronchodilation. However, while the fenoterol preparations caused tremors and a decrease in blood potassium levels, no such negative effects were seen with forskolin.
In another study, the bronchodilating effect (after five minutes) of forskolin was as good as that produced by fenoterol in 12 healthy volunteers (nonsmokers) as determined by whole body plethysmography. Both substances were administered by metered dose inhalers. At the beginning (after three and five minutes) the protective effect of forskolin against inhaled acetylcholine was as good as that produced by fenoterol while later on (after 15 and 30 minutes) fenoterol resulted in a stronger action. Whether orally administered forskolin in the for of C. forskohlii extract would produce similar bronchodilatory effects has yet to be determined. However, based onthe plant's historical use and additional mechanisms of action it is extremely likely.
Psoriasis
Psoriasis is an extremely common skin disorder that seems to be caused by a relative decrease in cAMP when compared to another cell regulating compound, cyclic guanine monophosphate (cGMP). The result is a tremendous increase in cell division. In fact, cells divide in psoriasis at a rate 1,000 times greater than the normal rate. Preliminary studies have indicated that forskolin may be of great benefit to individuals with psoriasis via its ability to normalize the balance that exists between cAMP and cyclic GMP.
Cardiovascular effects
Perhaps the most useful clinical applications of C. forskohlii extracts will turn out to be cardiovascular diseases such as hypertension, congestive heart failure, and angina. The cardiovascular effects of C. forskohlii and its components have been studied in great detail. Its basic cardiovascular actions involve lowering of blood pressure along with imporoved contractility of the heart. Again this is related to increasing cAMP levels throughout the cardiovascular system which results in relaxation of the arteries and increased force of contraction. The net effect is tremendous improvement in cardiovascular function. Several clinical and animal studies have suggested forskolin may significantly lower blood pressure as well as improve heart function in patients. In one human study involving seven patients with dilated cardiomyopathy, forskolin was shown to improve left ventricular function primarily via reduction of preload and without rising metabolic costs.
This study confirmed earlier animal studies which showed that forskolin increases the contractile force of heart muscle. In another human study, the hemodynamic effects of intravenous forskolin given to patients with dilated cardiomyopathy in a concentration of 3 mcg/kg/min was evaluated. Although systemic vascular resistance and diastolic pressure fell, forskolin had no effect on cardiac index, ejection fraction, or myocardial oxygen consumption at this very low dosage. However, when a small dosage of dobutamine was given along with the forskolin, and increase of all four parameters was observed. At a higher dosage (4 mcg/kg/min) forskolin induced an increase in impoved heart function by 19% and produced a 16% rise in heart rate. However, these changes were associated with symptomatic flush syndromes. These results indicate that forskolin may best be used in congestive heart failure in combination with other botanicals such as Crataegus species. Forskolin has also been shown to be a direct cerebral vasodialtor indicating that it may prove to be useful in cerebral bascular insufficiency and post-stroke recovery.
An aditional mechanism of action particularly beneficial in a wide range of cardiovascular conditions is inhibition of platelet aggregation. In this case some good evidence indicates the a standaridized C. forskohlii extract is superior to pure forskolin. In an animal model for evaluating in vivo inhibition of platelet aggregation rats were divided into four groups. Group 1 received C. forskohlii extract (480 mg/kg supplying 20 mg/kg of forskolin); Group 2 received forskolin (20 mg/kg), group 3 received dipyridamole; and Group 4 served as the control. All treatments were given orally once daily. ADP-induced platelet aggregation was measured on odd days 1 through 15. All three treatments produced significant inhibition of platelet aggregation. On day 15, the percent inhibition were approximately 42% for Group 1, 37% for Group 2, and 52% for Group 3. Hence, the extract of C. forskohlii produced greater inhibiiton than the pure forskolin.
Glaucoma
In clinical studies, forskolin has been shown to greatly reduce intra-ocular pressure (IOP) when it is applied directly to the eyes. This effect indicates that topical forskolin preparations may turn out to be of great benefit in the treatment of glaucoma. Unlike current drug therapy, forskolin actually increases intraocular blood flow, has no side effects, and does not induce miosis.
Other possible clinical applications
C. Forskohlii extracts concentrated and standardized for forskolin content may prove to be useful in a number of other clinical applications including weight-loss programs, hypothyroidism, malabsorption and digestive disorders, depression, prevention of cancer metastases, and immune system enhancement. Here's why.
Weight-loss programs:
Lipolysis, the breakdown of stored fat, in regulated by cAMP. Forskolin has been shown to stimulate lipolysis as well as inhibit the synthesis of fat in adipocytes. Forskolin has also been shown to counteract the decreased response of fat cells to lipolytic hormone like epinephrine associated with aging.
Hypothyroidism:
Forskolin has been shown to increase thyroid hormone production as well as stimulate thyroid hormone release.
Malabsorption and digestive disorders:
Forskolin stimulates digestive secretions including the release of hydrochloric acid, pepsin, amylase, and pancreatic enzymes. Forskolin has been shown to promote nutient absorption in the small intestine. C. forskohlii extracts may prove to be quite useful in treating dry mouth as forskolin increases salivation.
Depression:
Forskolin has been shown to exert antidepresant activity in animal studies.
Cancer metastases:
Forskolin has been shown to be a potent inhibitor of cancer metastasis in mice injected with malignant cells. As little as 82 mcg administered to mice inhibited metastases by over 70%.
Immune system enhancement:
Forskolin exhibits potent immune system enhancement (primarily through activation of macrophages and lymphocytes) in several models.
Dosage
The forskolin content of Coleus root is typically 0.2% to 0.3%, therefore the forskolin content of crude Coleus products may not be sufficient to produce a pharmacological effect. It is best to use standardized extracts which have concentrated the forskolin content. The recommended dosage should be based upon the level of forskolin. Future studies will undoubtedly produce more precise dosage recommendations of a Coleus forskohlii. The current recommendation for Coleus forskohlii extract, standardized to contain 185 forskolin, is 50 mg (9 mg of forskolin) two to three times daily. The animal studies on forskolin indicate an extremely low order of toxicity for forskolin. Based on the pharmacology of forskolin, it may be wide to restrict the use of C. forskohlii preparations in cases of low blood pressure and peptic ulcers. Furthermore, C. forskohlii preparations should be used with caution in patients on presription medications especially anti-asthmatics and anti-hypertensives due to its ability to possibly potentiate the drug's effect.
Summary
The ancient medicinal plant Coleus forskohlii is the source of the compound forskolin which possesses unique biological activity. While clinical results are thought to be better obtained using the whole plant versus the isolated constituent forskolin, research on forskolin is upholding the traditional uses of the plant. Due to the unique pharmacology of forskolin, C. forskohlii may prove to be useful in a wide range of clinical conditions. Presently, it appears C. forskohlii is best suited for asthma, eczema, psoriasis, hypertension, congestive heart failure, and angina. It can be used alone, but it may prove to be most useful when combined with other botanicals and/or other measures in the treatment of these disorders.
References:
1. Ammon HPT and Muller AB: Forskolin: from Ayurvedic remedy to a modern agent. Planta Medica 51:473-7, 1985
2. Seamon KB and Daly JW: Forskolin: a unique diterpene activator of cAMP-generating systems. J Cyclic Nucleotide Research 7:201-24, 1981
3. Dubey MP, Srimal RC, Nityand S and Dhawan hypotensive diterpene form Coleu forskohlii.. J ethnopharmacology 3:1-13, 1981
4. Lindner E, Dohawalla AN and bhattacharya BK: Positive inotropic and blood pressur lowering activity of a diterpene derivative isolated form coleus forskohli: forskolin. Arzneim.-Forsch 28:284-9. 1978
5. Hoffman BB, chang H and Reaven GM: Stimulation and inhibition of lipolysis in isolated rat adipocytes: Evidence for age-related changes in responses to forskolin and PGE1. Horm Metab Res 19:358-60, 1987
6. Roger PP, Servais P and Dumont JE. regulation of dog thyroid epithelial cell cycle by forskolin, and adenylate cyclase activator. Exp Cell Res 172:282-92, 1990
7. Chang J, et al: effect of forskolin on prostaglandin synthesis by mouse resident pertoneal macrophages. european J Pharmacology 103:303-12, 1984"
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