Coleus (Coleus forskohlii)
Synonyms / Common Names / Related Terms
Coleon U-quinone coleus, coleonol, Coleus amboinicus Lour (CA), Coleus barbatus Benth, Coleus blumei, Coleus blumei Benth, Coleus carnosifolius, Coleus galeatus, Coleus kilimandschari, Coleus parvifolius, Coleus scutellarioides, coleus solenostemon rotundifolius, Coleus xanthanthus, colforsin, colforsin daropate hydrochloride, forscolin, forskoditerpenoside A, forskoditerpenoside B, forskolin, forskolin G, forskolin H, HL 362, FSK88, Labiatae (family), Lamiaceae (family), L-75-1362B, NKH477, Plectranthus barbatus, Plectranthus forskohlii, rosmarinic acid, rosemary, rosmarinic acid, xanthanthusin E, xanthanthusins F-K.
Mechanism of Action
- Constituents: The most important constituents of rosemary are caffeic acid and its derivatives, such as rosmarinic acid. These compounds have antioxidant effects. 21Diterpenoids, such as coleon U 11-acetate, 16-acetoxycoleon U11-acetate, xanthanthusins F-K, plus analogues, coleon U, 16-O-acetylcoleon C, coleon U-quinone, 8alpha, 9alpha-epoxycoleon U-quinone, and xanthanthusin E, have been isolated from the aerial parts of Coleus xanthanthus.22 Forskolins G-J were isolated from the whole plant of the Coleus forskohlii Briq.23,24 13-epi-sclareol was isolated from the roots of Coleus forskohlii.25 Diterpene glycosides, forskoditerpenosides A, B and an eudesmane sesquiterpene, 4beta, 7beta, 11-enantioeudesmantriol, were isolated from the ethanol extract of the whole plant of Coleus forskohlii. Six compounds were obtained in the root of Coleus forskohlii and the structures were identified as 14-deoxycoleon U, demethylcryptojaponol, alpha-amyrin, betulic acid, alpha-cedrol and beta-sitosterol.26
- The effective range of the competitive enzyme-linked immunosorbent assay (ELISA) test for detection of forskolin content in clonally propagated plant organs of Coleus forskohlii using monoclonal antibodies extends from 5ng to 5mcg. A correlation between the forskolin accumulation and the growth rate was investigated using the clonally propagated shoots. Flowers, rachises, leaves, stems, tuberous roots, and roots were analyzed. Tuberous roots and the stem base contained higher amounts of forskolin than other organs. The forskolin content in the stem decreased gradually towards the top of the shoot.27
- Adenylyl cyclase effects: Forskolin is a diterpene derivative and activates the enzyme adenylate cyclase to promote the generation of cyclic adenosine monophosphate (cAMP).28 cAMP is a cell-regulating compound that stimulates various enzymes involved in a broad range of cellular function, including energy production. Activation of adenylate cyclase by forskolin correlates with its positive cardiotonic (inotropic) and vasodilator effects.20 Forskolin directly stimulates the catalytic unit of adenylate cyclase independently of any receptor mediated mechanism of action.7
- Antidepressant effects: Several different treatments alleviate depressive disorders by increasing the activity of adenylyl cyclase, involving enhancement of the cAMP signal transduction system. Forskolin increased swimming activity in rats and delayed immobility in the same way as the tricyclic drug amitriptyline. Results suggest increasing cAMP may exert an antidepressant effect.29
- Forskolin decreased locomotor activity, reduced body temperature, and increased grooming activity and head twitches in a dose-dependent manner in rats following intraperitoneal administration. These effects were more apparent when forskolin was combined with rolipram, a cAMP-selective phosphodiesterase inhibitor that has antidepressant activity and increases availability of cAMP in the brain like forskolin.30
- Antidiabetic effects: Colenol, a diterpenoid isolated from the roots of Coleus forskohlii stimulated the release of insulin and glucagon from the islets both in vitro and in vivo .16 Colenol-stimulated release of glucagon from islets in vitro was more pronounced as compared to that of insulin. Glucose concentration of 5.6mM in the medium is required for the colenol stimulation of insulin release. Feeding of coleonol to alloxan diabetic rats caused 36.5% increase in blood glucose level as compared to alloxan diabetic control. Oral feeding of coleonol for seven days to normal rats caused an increase in blood glucose, serum insulin, glucagon and free fatty acid levels with corresponding increase in glucose-6-phosphatase activity and depletion of liver glycogen. Predominant stimulation of A-cells by coleonol is suggested for the above effects.
- Antidrepanocytary activity (anti-sickle cell anemia activity): The leaves of Coleus kilimandcharis demonstrated antidrepanocytary activity.31
- Antihistamine effects: Exposure of lung fragments to forskolin inhibited the antigen-induced release of histamine and leukotrienes to similar extent in an in vitro study using guinea-pig lung. Combining forskolin with isoproterenol resulted in a stronger inhibition of histamine release. Researchers concluded that increased cAMP suppresses histamine release in response to antigenic exposure. The concentration of forskolin needed to inhibit histamine and leukotriene release is comparable to that required to stimulate adenylate cyclase.32
- Another in vitro study based on leukocytes from allergic individuals showed that forskolin inhibited the release of histamine and leukotriene C4 from basophils exposed to immunoglobulin E (IgE) in a concentration-dependent manner. The same effect was noted on mast cells isolated from human lung tissue. Inhibition of leukotriene release was significantly greater than the effect on histamine release in both instances. Inhibition was paralleled by an increase in levels of cAMP in both leukocytes and mast cells. The inhibitory effects of forskolin were not changed by exposure to propranolol, a beta-blocker. Forskolin may prevent antigen-induced allergic reactions because chemical mediators released by IgE-dependent immune activation of these cells may play an important role in development of allergic disorders.1
- Antihypertensive effects: Dubey et al. extensively reported the pharmacological profile of coleonol, isolated from a 50% ethanol extract of Coleus forskohlii.17 Coleonol is a distereoisomer of forskolin. The predominant effect of coleonol lowered the blood pressure of anesthetized cats and rats, as well as spontaneously hypertensive rats, due to the relaxation of the vascular smooth muscle. In small doses it has a positive inotropic effect on isolated rabbit heart as well as on the cat heart in vivo. Coleonol exhibits nonspecific spasmolytic activity on smooth muscle of the gastrointestinal tract in various species, but not on bronchial musculature of guinea pigs. Large doses of coleonol have a depressant action on the central nervous system. In addition, forskolin, a stereoisomer of coleonol, has more pronounced positive inotropic activity than coleonol.15 Forskolin also lowered blood pressure and increased heart rate in animals.15
- Antimetastatic and antiproliferative effects: Forskolin, prostacyclin, and ketoconazole significantly reduced tumor surface area and the number of tumor colonies after intrasplenic injection of the tumor cells in an in vivo study of mice bearing human pancreatic adenocarcinoma cells derived from a liver metastasis. The study examined the effects on tumor growth of forskolin and prostacyclin, both stimulators of platelet adenylate cyclase, and ketoconazole, which inhibits lipoxygenase and thromboxane synthetase. These agents also strongly inhibited platelet aggregation in human platelet-risk plasma, suggesting that they exert their anti-metastatic effect by interfering with platelet-tumor cell interactions. The exact means by which platelets enhance metastasis remains unclear.33
- It has been suggested that many metastasizing tumor-cell lines induce platelet aggregation and that, when aggregated, platelets release a substance or substances that promote tumor growth. This possibility gains support from a study in which forskolin strongly inhibited the aggregation of human platelets exposed to murine melanoma cells (which tend to spread to the lungs). A single injection, given within one hour before injecting cultured tumor cells, reduced tumor colonization of the lungs by more than 70%.3
- When isolated from the roots of Coleus forskohlii, 13-epi-sclereol showed antiproliferative activity in breast and uterine cancers in vitro.25 The antiproliferative activity of 13-epi-sclareol is comparable to tamoxifen in terms of IC50 and also showed concentration dependent increased apoptotic changes in the breast cancer cell line, MCF-7.
- A forskolin derivative, FSK88, induced apoptosis in human gastric cancer BGC823 cells through caspase activation involving regulation of Bcl-2 family gene expression, dissipation of mitochondrial membrane potential, and cytochrome c release.34
- Forskolin inhibited the caspase enzyme activity in vivo and consequently the rapid cell death process.35
- Anti-obesity effects: The anti-obesity effects of Coleus forskohlii were investigated in ovariectomized (ovx) rats.8 Eight-week-old female Wistar rats were assigned to one of four groups: a sham-operated group fed the control diet (MF, sham-m); an ovx-m group fed the control diet; a sham-operated group fed the control diet containing 50g/kg of Coleus forskohlii extract (sham-c); or an ovx-c group fed the control diet containing 50g/kg of Coleus forskohlii extract. The body weight, adipose tissues, and cell diameter were investigated in ovx rats after Coleus forskohlii extract treatment. Administration of Coleus forskohlii extracts reduced body weight, food intake, and fat accumulation in ovx rats.
- Water-soluble extract of Coleus barbatus modulated weight gain, energy utilization and lipid metabolism in secondary biliary cirrhosis in an experimental study in young rats.4
- Antioxidant effects: A preliminary study was conducted to elucidate in vitro free radical scavenging potential and inhibition of lipid peroxidation of Coleus aromaticus hydroalcoholic extract.2 Coleus aromaticus hydroalcoholic extract at 10, 20, 40, 60, 80, 100, and 120mcg/mL resulted in a dose-dependent increase in radical scavenging ability against various free radicals viz., 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), superoxide anion (O(2)(*-)), hydroxyl (OH(*)) and nitric oxide (NO(*)) generated in vitro. A maximum scavenging potential was noticed at 100mcg/mL, and a saturation point was reached thereafter with the increasing doses of Coleus aromaticus hydroalcoholic extract. The free radical scavenging potential of the extract was in the order of DPPH > ABTS > Superoxide > Hydroxyl > Nitric oxide. Coleus aromaticus hydroalcoholic extract also exhibited a moderate inhibition of lipid peroxidation in vitro, with a maximum inhibition at 60mcg/mL (33%), attaining saturation at higher doses. The extract also rendered protection against radiation induced DNA damage, as evidenced by the significant (p<0.05) decrease in the percentage of radiation-induced micronucleated cells (MN) and frequency of micronuclei (total). A maximum anticlastogneic effect/radioprotection was noticed at a very low concentration, i.e., 5mcg/mL of Coleus aromaticus hydroalcoholic extract, treated one hour prior to 2Gy of gamma radiation. A significant (p<0.0001) anticlastogenic/radioprotective effect was also observed when the cells were treated with an optimum dose of Coleus aromaticus hydroalcoholic extract (5mcg/mL) one hour prior to 0.5, 1, 2, and 4 Gy of gamma radiation compared with the respective radiation control groups.
- Breast milk-stimulating effects: Lactating women who received Coleus amboinicus Lour had an increase in milk volume during the first month of lactation; however, the mechanism of action is not fully understood.13
- Bronchodilation effects: Forskolin produced a concentration-dependent inhibition of histamine release from pulmonary mast cells exposed to IgE, at the same time as intracellular levels of cAMP were increasing. Forskolin appears to modulate the release of mediators of immediate hypersensitivity reactions via the activation of adenylate cyclase in human basophils and mast cells.1
- Forskolin relaxes airway smooth muscle and inhibits mediator release in vitro and elicits bronchodilation in vivo. Bronchospasm induced by inhaled antigen in sensitized guinea pigs was prevented in a dose-related fashion by the intravenous or intratracheal administration of forskolin. In vitro forskolin inhibited contractions of lung parenchyma provoked by histamine, LTC4 or antigen. Forskolin also inhibited the immunologically stimulated release of LTD4 and histamine from sensitized guinea pig lungs.36 Forskolin was found to be more potent than aminophylline and less potent than salbutamol.36
- Cardiovascular properties: Lindner et al. established the positive inotropic activity of forskolin on the isolated guinea pig heart, on the isolated left atrium of the guinea pig heart, and on the dog and cat heart in situ.15 It increased the heart rate, whose action was not blocked by beta-blockers. Forskolin lowers the blood pressure in dogs and cats and also in spontaneously hypertensive and renal hypertensive rats.
- Dubey et al. extensively reported the pharmacological profile of coleonol, isolated from a 50% ethanol extract of Coleus forskohlii.17 Coleonol is a distereoisomer of forskolin. The predominant effect of coleonol was to lower the blood pressure of anesthetized cats and rats as well as spontaneously hypertensive rats due to relaxation of the vascular smooth muscle. In small doses it has a positive inotropic effect on isolated rabbit heart as well as cat heart in vivo. Coleonol exhibits nonspecific spasmolytic activity on smooth muscle of the gastrointestinal tract in various species, but not on bronchial musculature of guinea pigs. Large doses of coleonol have a depressant action on the central nervous system. In addition, forskolin, a stereoisomer of coleonol, has more pronounced positive inotropic activity than coleonol.15
- Lindner et al. established the positive inotropic activity of forskolin on the isolated guinea pig heart, on the isolated left atrium of the guinea pig heart and on the dog and cat heart in situ.15 It increased the heart rate, whose action was not blocked by beta-blockers. Forskolin lowers the blood pressure in dogs and cats and also in spontaneously hypertensive and renal hypertensive rats.
- Unlike other drugs that promote the contractility of cardiac muscle, such as the digitalis glycosides, forskolin does not directly inhibit sodium-potassium-ATPase. The two types of agents are equally effective in depleting muscle tissue of potassium. Part of the action of forskolin appears to derive from its activation of adenylate cyclase, followed by augmentation of cAMP, activation of a cAMP-dependent protein kinase, phosphorylation of a protein or enzyme, and inhibition of sodium-potassium-ATPase activity. These events may lead to imposed sodium and calcium exchange across the cell membrane along with a rising intracellular calcium concentration and positive inotropy.37
- Isolated human myocardium from patients with normal hearts and end-stage heart failure had improved contractility when exposed to forskolin.38
- Vasodilation of the rat-tail artery by forskolin seems to occur primarily by changes in repolarization and decreased sensitivity to intracellular calcium.39
- Two actions of forskolin may explain its beneficial effects in patients with idiopathic congestive cardiomyopathy - a marked vasodilator effect on venous capacitance vessels and arterial resistance vessels and a direct inotropic effect on the heart. Positive inotropic actions have been demonstrated both in vitro and in intact animals. Neither the inotropic nor the vasodilatory effect of forskolin is antagonized by blocking beta-receptors or H2-receptors.
- Cloning and molecular genetics: Molecular cloning and functional expression of geranylgeranyl diphosphate (GGPP) synthase was studied in Coleus forskohlii Briq.40 Forskolin was synthesized by a non-mevalonate pathway, and GGPP synthase was involved in the biosynthesis of forskolin, which is primarily synthesized in the leaves and subsequently accumulates in the stems and roots.
- Cytochrome P450 and nuclear receptor effects: Cytochrome P450 enzymes are often mediated by nuclear receptor superfamily members designated PXR (pregnane X receptor). Activation of PXR represents the basis for several clinically important drug-drug interactions.6 Although PXR activation has undesirable effects in patients on combination therapy, it also mediates the hepatoprotective effects exhibited by some herbal remedies. Forskolin and its nonadenyl cyclase-activating analog 1,9 dideoxyforskolin induce CYP3A gene expression in primary hepatocytes by functioning as agonists of PXR.5 The activation of PKA signaling potentiated PXR-mediated induction of CYP3A gene expression in cultured hepatocytes and increases the strength of PXR-coactivator protein-protein interaction in cell-based assays. Kinase assays showed that PXR could serve as a substrate for catalytically active PKA in vitro.
- Hepatoprotective effects: PXR, NR1I2 activation may mediate the proposed hepatoprotective effects exhibited by Coleus forskolii.6
- Nitric oxide scavenging: Coleus ambonicus was found to have nitric oxide scavenging properties in vitro.41
- Ocular effects: Caprioli et al. demonstrated that topical forskolin significantly reduces intraocular pressure (IOP) in rabbits, monkeys and humans.9 It is also reported in animal studies that forskolin decreased the net aqueous humor inflow, left the outflow facility unchanged, and increased the ciliary blood flow.10,42,11,43 Tolerance to the IOP lowering effect did not occur in rabbits after topical doses given every six hours for 15 days. Forskolin reduced significantly the normal IOP of rabbits; the peak reduction was after 2-3 hours, and it remained significantly for 10 hours. The effect was dose dependent.44,45 When the ocular penetration of forskolin in suspension was investigated, it was shown that only 0.03% of the instilled forskolin penetrated the ocular tissue.46 The weak IOP lowering effect of topical forskolin suspension was considered to be due to its poor ocular penetration.
- Platelet aggregation properties: Binding sites for forskolin have been described in human platelet membranes. Forskolin leads to disaggregation of platelets to a degree that correlates with the increase in cAMP. This property of forskolin has been exploited to prevent thrombosis in small-caliber grafts of synthetic material such as polytetrafluoroethylene by impregnating the grafts with an ethanolic solution.47,48 In an in vivo sheep model, intra-arterially infused forskolin affected blood flow and platelet parameters favorably in the setting of occlusive arterial disease and reconstructive arterial surgery.14 In rabbit study, the action of forskolin on platelet-activating factor receptor binding was independent of adenylyl cyclase or G-protein involvement, but was due to a direct effect of this molecule on the PAF receptor itself.49
- Relaxative effects: Forskoditerpenosides A and B, two minor diterpene glycosides isolated from Coleus forskohlii, showed relaxative effects on isolated guinea pig tracheal spirals in vitro.50
- Renal effects: A forskolin-like molecule has been identified in human renal cysts.12 Therefore, forskolin may place a role in the enlargement of cysts in autosomal dominant polycystic kidney disease, although the mechanism remains unclear.
- Thyroid effects: Based on laboratory study, forskolin and thyrotropin appear to upregulate Gs protein subunits.18 Saunier et al. suggested that their synthesis in thyroid cells is mediated, at least in part, by a cyclic AMP-dependent mechanism.
- Vasculogenic properties: There is promising evidence suggesting that forskolin can be used as an addition to a standard 3-agent pharmacotherapy for vasculogenic impotence (erectile dysfunction).51 There is also in vitro and in vivo animal research that supports a possible role of forskolin treating this condition.52 In vivo experiments on male mongrel dogs showed with forskolin as well as with prostaglandin E1 concentration-dependent increases in both the magnitude and the duration of intracorporeal pressure, up to a maximum of 80-90% of mean arterial pressure.
- Absorption: Forskolin is minimally soluble in water and bioavailability is poor after oral administration.19 Absorption was studied in cats, and intraduodenal administration produced hypotension of about the same degree as observed after intravenous administration except for a latency interval of 3-6 minutes.17
- Distribution: Distribution studies were performed in rats by injecting 3H-labeled forskolin (0.036mg/kg) intravenously and a water-soluble forskolin derivative called 14C-labeled NKH477 (0.039mg/kg). The animals were killed one minute after injection. At that time, the distribution of NKH477 in most brain regions was lower than that of forskolin. The pituitary was an exception, containing more NKH477 than forskolin.19
- Metabolism: The induction of drug metabolism of forskolin was evaluated and PXR and the protein kinase signal transduction pathway were found to play a role.5
- Initial response: Initial response following a single intravenous dose of 30mcg/kg of forskolin in dogs caused an immediate decline in mean arterial pressure.20
- Peak response: Peak response following intravenous administration for blood pressure reduction occurred within 5-10 minutes.20
- Duration: The fall in mean arterial pressure after single intravenous dose of forskolin lasted 30 minutes.20
- Marone, G., Columbo, M., Triggiani, M., Cirillo, R., Genovese, A., and Formisano, S. Inhibition of IgE-mediated release of histamine and peptide leukotriene from human basophils and mast cells by forskolin. Biochem Pharmacol 1-1-1987;36(1):13-20. 2432900
- Rao, B. S., Shanbhoge, R., Upadhya, D., Jagetia, G. C., Adiga, S. K., Kumar, P., Guruprasad, K., and Gayathri, P. Antioxidant, anticlastogenic and radioprotective effect of Coleus aromaticus on Chinese hamster fibroblast cells (V79) exposed to gamma radiation. Mutagenesis 2006;21(4):237-242. 16735450
- Agarwal, K. C. and Parks, R. E., Jr. Forskolin: a potential antimetastatic agent. Int J Cancer 12-15-1983;32(6):801-804. 6686215
- Battochio, A. P., Sartori, M. S., and Coelho, C. A. Water-soluble extract of Coleus barbatus modulates weight gain, energy utilization and lipid metabolism in secondary biliary cirrhosis: an experimental study in young rats. Acta Cir Bras 2005;20(3):229-236. 16033182
- Ding, X. and Staudinger, J. L. Induction of drug metabolism by forskolin: the role of the pregnane X receptor and the protein kinase a signal transduction pathway. J Pharmacol Exp Ther 2005;312(2):849-856. 15459237
- Staudinger, J. L., Ding, X., and Lichti, K. Pregnane X receptor and natural products: beyond drug-drug interactions. Expert Opin Drug Metab Toxicol 2006;2(6):847-857. 17125405
- Baumann, G., Felix, S., Sattelberger, U., and Klein, G. Cardiovascular effects of forskolin (HL 362) in patients with idiopathic congestive cardiomyopathy--a comparative study with dobutamine and sodium nitroprusside. J Cardiovasc Pharmacol 1990;16(1):93-100. 1696672
- Han, L. K., Morimoto, C., Yu, R. H., and Okuda, H. Effects of Coleus forskohlii on fat storage in ovariectomized rats. Yakugaku Zasshi 2005;125(5):449-453. 15863977
- Caprioli, J. and Sears, M. Forskolin lowers intraocular pressure in rabbits, monkeys, and man. Lancet 4-30-1983;1(8331):958-960. 6132271
- Caprioli, J., Sears, M., Bausher, L., Gregory, D., and Mead, A. Forskolin lowers intraocular pressure by reducing aqueous inflow. Invest Ophthalmol Vis Sci 1984;25(3):268-277. 6538189
- Burstein, N. L., Sears, M. L., and Mead, A. Aqueous flow in human eyes is reduced by forskolin, a potent adenylate cyclase activator. Exp Eye Res 1984;39(6):745-749. 6542866
- Putnam, W. C., Swenson, S. M., Reif, G. A., Wallace, D. P., Helmkamp, G. M., Jr., and Grantham, J. J. Identification of a forskolin-like molecule in human renal cysts. J Am Soc Nephrol 2007;18(3):934-943. 17251383
- Damanik, R., Wahlqvist, M. L., and Wattanapenpaiboon, N. Lactagogue effects of Torbangun, a Bataknese traditional cuisine. Asia Pac J Clin Nutr 2006;15(2):267-274. 16672214
- Christenson, J. T., Thulesius, O., and Nazzal, M. M. The effect of forskolin on blood flow, platelet metabolism, aggregation and ATP release. Vasa 1995;24(1):56-61. 7725780
- Lindner, E., Dohadwalla, A. N., and Bhattacharya, B. K. Positive inotropic and blood pressure lowering activity of a diterpene derivative isolated from Coleus forskohli: Forskolin. Arzneimittelforschung 1978;28(2):284-289. 580393
- Ahmad, F., Khan, M. M., Rastogi, A. K., and Kidwai, J. R. Insulin and glucagon releasing activity of coleonol (forskolin) and its effect on blood glucose level in normal and alloxan diabetic rats. Acta Diabetol Lat 1991;28(1):71-77. 1650516
- Dubey, M. P., Srimal, R. C., Nityanand, S., and Dhawan, B. N. Pharmacological studies on coleonol, a hypotensive diterpene from Coleus forskohlii. J Ethnopharmacol 1981;3(1):1-13. 7193263
- Saunier, B., Dib, K., Delemer, B., Jacquemin, C., and Correze, C. Cyclic AMP regulation of Gs protein. Thyrotropin and forskolin increase the quantity of stimulatory guanine nucleotide-binding proteins in cultured thyroid follicles. J Biol Chem 11-15-1990;265(32):19942-19946. 2174058
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