Chemistry

Forskolin, obtained from the root of the extract of Coleus forskholii, is an oily di-labdane terpene. Forskolin has received much attention due to its ability to stimulate a membrane bound enzyme . Adenylate Cyclase (AC). Prior to forskolin.s discovery, there was no known activator of this enzyme. Adenylate Cyclase (AC) is an enzyme-system-complex, with various activating catalytic units and sub-units embedded in the membrane bi-layers of numerous tissues including the myocardium, bronchioles, arteries, kidneys, etc. AC has two polar sub-units . the catalytic C unit and the nucleotide regulatory sub-unit N. Forskolin directly stimulates the C subunit, resulting in stimulation of cyclic adenosine mono phosphate (cAMP), which in turn activates and elicits a cascade of enzymatic functions. cAMP is an important second messenger, one of the most vital regulatory compounds in the cell.

Forskolin is a remarkably targeted botanical with unique and extensive pharmacological properties for cellular regulation, biological response modification and the fine tuning numerous enzymatic reactions.


Pharmacology - Cardiology

(1) Increases Contractility.
Forskolin is a potent inotropic agent. Stimulation of cAMP production increases the contractility of the myocardium. Beta adrenergic agonists are potent pharmacologic agents in this regard and have been used therapeutically in the treatment of heart failure. However, such compounds have a major disadvantage that limits their long-term use. Continuous exposure to beta-agonists renders the myocardium sub-sensitive by reducing beta-receptor density and/or receptor-cyclase coupling. Both of these sub-sensitivity phenomena are apparently regulated through the N sub-unit of AC. Forskolin, however, acts primarily via the C-sub-unit and does not demonstrate the subsensitive phenomena or beta-receptor down-regulation. Indeed forskolin exhibits positive inotropic and chronotropic characteristics, as seen in the guinea pig, sheep, rat, pig, rabbit and humans.

2) Inhibition of Platelet Aggregation.
Inhibition of platelet aggregation has beneficial effects on morbidity and mortality. Forskolin stimulates platelet AC, resulting in increased cAMP and a corresponding decrease in platelet aggregation.

3) Inhibits Thrombosis.
Forskolin produces deaggregation of aggregated human platelets in-vitro and may offer an important prophylactic treatment in preventing thrombosis.

4) Hypertension.
Forskolin was shown to be a potent vasodilator in a dose-dependent manner. Forskolin induced vasodilation similar to isoproterenol, a potent beta-agonist. Forskolin significantly decreased preload and afterload and improved left ventricular function.


Allergic Conditions

(1) Asthma
Low cAMP levels have an association with high incidence of allergic reactions, including eczema, psoriasis, and asthma. Forskolin elicits anti-asthmatic activity via the following:

(2) Relaxes bronchial smooth muscle by increasing cAMP (an effect comparable with a prescription drug fenoterol, though the effect was not as long lasting).

(3) Inhibits Platelet Activating Factor (PAF) by competitive inhibition. PAF has the following properties: increased bronchial permeability and smooth muscle contraction. A 40% decrease in PAF binding was observed after pretreatment with forskolin. This antagonistic action on PAF by forskolin is not via the stimulation of cAMP, but by another direct stimulation mechanism.

(4) Psoriasis. In psoriasis, cyclic guanine monophosphate (cGMP), another secondary messenger and regulator of cellular action, is greatly increased compared to cAMP. By stimulating cAMP levels, the cGMP/cAMP ratios are reduced to normal levels. High cGMP are associated with a high rate of cellular division, a characteristic of psoriasis.


Other Biological Actions

Glaucoma - Topical preparation of forskolin greatly reduced intraocular pressure without inducing miosis.

Hypothyroidism - Increases thyroid hormone production and release.

Anti-Inflammatory - PAF is a potent inflammatory agent, activating neutrophils and increasing vascular permeability. Forskolin is a potent inhibitor of PAF via a unique non-cAMP mechanism.

Antispasmodic - Forskolin is a potent relaxer of smooth muscles. Useful in angina, intestinal cramps, difficulty in bladder emptying, etc. Weight loss - Forskolin, like B-agonists, stimulates lipolysis via increased cAMP levels, an effect possible through increased thermogenesis and improved thyroid activity.

Salivation - Increases saliva output (useful in treating conditions associated with dry mouth).

Forksolin should be produced as a full-spectrum, optimally-standardized product verified by HPLC. 4% Forskolin content is the maximal amount extractable without compromising the quality and exclusion of other beneficial compounds. Personal communication with one of the original (and leading) researchers at Hoechst Pharmaceutical, Bombay, India (where the original work was done) has revealed that an extract above 4% results in a less effective product due to the loss of other beneficial molecules. Chemical synthesis has been utilized to produce higher forskolin content, but without achieving similar therapeutic efficiency to a 4% extract.