Forskolin

Scientific Name(s): Plectranthus barbatus . Lamiaceae (mint family)

Common Name(s): Forskolin , HL-362 , Indian coleus , makandi , mao hou qiao rui hua , NKH477 , and pashanabhedi . A forskolin derivative, Colforsin daropate , is registered for use in Japan as Adel Inj . The plant is a component of commercial preparations, including Asthma X-5 , Ele-max , Interex , Meta-Burn EF , GlucoLean , and ForsLean .

Uses

Forskolin has multiple sites of action and should be used with caution. Forskolin derivatives have been developed for use in cardiovascular conditions. Quality clinical trials are lacking to substantiate claims made of the weight loss properties of forskolin, and clinical studies conducted with oral and inhaled forskolin in patients with asthma are limited.

Dosing

Asthma : Oral forskolin has been studied using 10 mg daily over 2 to 6 months. Obesity : 250 mg of a 10% forskolin extract twice daily for 12 weeks has been studied.

Contraindications

Case reports are lacking.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. P. barbatus has been traditionally used as an emmenagogue and oral contraceptive.

Interactions

None well documented.

Adverse Reactions

Clinical trial data are generally lacking. Adverse events reported with the use of colforsin (a forskolin derivative) include tachycardia and arrhythmias. Forskolin should be avoided in patients with polycystic kidney disease.

Toxicology

Information is limited. Embryo-related toxicity has been reported.

Botany

P. barbatus is a perennial herb in a large genus of mints. Some of the species within the genus are difficult to distinguish, leading to unclear taxonomy. Synonyms include Plectranthus forskalaei , Plectranthus forskohlii , Plectranthus kilimandschari , Plectranthus grandis , Coleus forskohlii , Coleus barbatus , and Coleus coerulescens .

The plant is native to subtropical and tropical regions of India and East Africa, grows to a height of 60 cm, and has large, soft leaves. Clustered purple-blue flowers appear from fall to late spring. 1 , 2 , 3

History

This species and other related species have been used extensively in many traditional medical systems, including those of Brazil, eastern, and central Africa, as well as India and other Asian countries. Traditional medical uses include the treatment of digestive disorders (stomachache, gastric and intestinal spasm, nausea, as a purgative), skin (burns, wounds, insect bites, allergies), infections (eg, syphilis, ringworm), and other conditions, including neck stiffness, and rheumatism, and as an emmenagogue and oral contraceptive. Forskolin has also been used to treat heart, blood, and circulation conditions, and cancers. In the 1970s, the plant's cardiovascular activity was investigated, while the discovery that the diterpene forskolin directly activates adenylate cyclase (AC) was also made. 2 , 3 , 4 Research is largely limited to the use of radiolabeled forskolin to quantify AC and to investigate analogs of forskolin. In India, the plant is cultivated for use in pickles. 3 , 5 , 6

Chemistry

The main constituents of P. barbatus are the diterpenoids and essential oil. Content of the essential oil depends on location and time of harvesting, and mainly consists of mono- and sesquiterpenes. Approximately 70 diterpenoids have been described in the leaves, roots, and whole plant, with forskolin (also known as coleonol) being one of the most active compounds. 3

Because forskolin has been actively pursued as a drug development lead, many analytical chemistry studies exist, and commercially available preparations can be standardized by forskolin content. 3 Tissue culture methods for forskolin production have also been successfully explored because the relatively modest content of forskolin in the plant has limited its development as a drug. 7 , 8

Uses and Pharmacology

The principle mechanism by which forskolin exerts its activity is by stimulation of AC, thereby increasing cellular cAMP, which is involved in processes such as glycogen and lipid metabolism. Chemical modification of forskolin at the 6- and 7-positions has led to semisynthetic compounds, with modest selectivity for particular cyclase isoforms, including the cardiac type 5 AC.

Stimulation of AC is thought to be the mechanism by which forskolin relaxes a variety of smooth muscles; however, forskolin has been found to act through other systems, including glucose transport and ion channels. 4 , 5 , 6 , 9 , 10

Antithrombotic effect

Forskolin has been shown in vitro to inhibit platelet aggregation through AC stimulation, augmenting the effects of prostaglandins. 11 , 12 An inhibitory effect on C-kinase activation in platelets has also been described. 6

Animal data

Antithrombotic properties have been demonstrated in experiments in rats, rabbits, and sheep. 6

Clinical data

Research reveals no clinical data regarding the use of forskolin for antithrombotic effects.

Cardiovascular effects
Animal data

Positive inotropic action has been demonstrated in isolated guinea pig, rabbit, and human heart tissue, and in vivo in cats and dogs. Forskolin augmented coronary blood flow in guinea pig hearts and increased heart rate and decreased blood pressure in dogs, cats, rabbits, and rats. A concentration-dependent inhibition of vascular contractility was demonstrated in rat aorta, and a vasodilator action in rats and rabbits has been shown. 6

Clinical data

In human heart tissues, forskolin activated AC and demonstrated strong positive inotropic properties that were synergistic with isoproterenol. 13 Older, small clinical studies have demonstrated that forskolin improves coronary blood flow and myocardial and left ventricular function and increases the blood flow in the cerebrum and kidneys. 6

Due to poor water solubility and low oral bioavailability, clinical use of forskolin is limited and has led to development and study of colforsin ( NKH477 ), a water-soluble derivative. Colforsin has a higher affinity for type 5 AC (myocardial AC), does not appear to cross the blood-brain barrier, and exerts a longer duration of action than forskolin. A colforsin preparation ( Adehl ) is approved for use in Japan, and limited studies have been conducted in cardiac surgery, heart failure, and cerebral vasospasm. 6 , 14 , 15 , 16

CNS

The use of forskolin in studies involving the CNS is largely related to elucidating the role of cAMP in depression and other cellular processes. 17 , 18 , 19

Animal data

Radiolabeled forskolin was shown to bind to rat brain membranes in a saturable and specific manner. 20 Forskolin demonstrated potent antidepressant activity in a rat forced swimming model 21 and prevented induced seizures in mice. 6

Clinical data

Clinical trials are lacking; however, case studies using intravenous infusions of forskolin demonstrated a transient elevation in mood in some depressed and schizophrenic patients. 6

Obesity

A patent claiming promotion of lean body mass and antidepressant activity of a forskolin-containing extract was granted to the supplement company Sabinsa in 1998, and another patent was awarded in 2006. 6 , 22

Animal data

Animal models of obesity have been used by the patent holder to demonstrate decreases in body weight and fat. 6 In vitro studies suggest forskolin acts via cAMP but in a more complex manner than that of increased AC levels. 6 , 23

Clinical data

Quality clinical trials are lacking to substantiate claims made of the antiobesity properties of forskolin. Two older studies suggested that topically applied forskolin cream reduced localized fat in the thighs of obese women without the need for diet or exercise. 6 A small (N = 30), randomized clinical trial conducted in obese men found a decrease in body fat, increase in bone mass, and a trend toward changes in lean body mass following 12 weeks of forskolin versus placebo. An increase in serum testosterone was also demonstrated. 24 Adverse events were not reported. A trial conducted among women at the same dosage found no changes in body fat and concluded that forskolin does not promote weight loss. No changes in various metabolic markers or laboratory indices were found, except for changes in white blood count, serum calcium, ALT, and uric acid levels. 25

Respiratory

In addition to smooth muscle relaxant properties, forskolin also exerts activity on inflammatory mediators, including interleukins and histamine, and on calcium ion influx, leading to its evaluation in asthma. 6 , 26

Animal data

In guinea pigs, forskolin blocked bronchospasm caused by inflammatory mediators (histamine, leukotriene-4) and antigens. Relaxation of the bronchioles has also been demonstrated in isolated ovine tissue. 6

Clinical data

Limited single-blinded clinical studies have been conducted with oral and inhaled forskolin in patients with asthma and in healthy volunteers. Oral forskolin performed better than sodium chromoglycate in preventing asthma attacks in children and adults with mild/moderate persistent asthma, while inhaled forskolin was not superior to beclomethasone in lung function improvement. Adverse events were not reported. 26 , 27 Colforsin has also been evaluated as a bronchodilator in a limited number of studies. 28 , 29 , 30

Skin
Animal data

Studies in animals have shown various effects of forskolin, including induction of melatonin production in the pineal glands, increased melanin in hair follicles leading to an increase in pigmentation, increased hair growth, and a protective effect against ultraviolet B light (UBV)-induced apoptosis. 6 , 31 , 32 , 33

Clinical data

Case reports exist showing improvement of psoriatic symptoms and a decrease in erythema in patients with hyperplastic skin disorders. 6

Other uses
Cancer

Experimental studies on various cancer cell lines have shown synergistic effects of forskolin in upregulating cellular responses. 32 , 34 , 35 , 36 , 37 , 38 A protective effect against ionizing radiation 39 and UBV-induced apoptosis 33 has been shown in vitro. Forskolin has been demonstrated to have an angiogenic effect via cAMP-dependent protein kinase pathways. 40

Diabetes

Stimulation of the release of pancreatic insulin and glucagon by forskolin has been demonstrated in vitro. 6 Influence of forskolin on glucose transport and the action of insulin in skeletal muscle has also been described. 41 , 42 , 43 Clinical trials are lacking; however, studies in normal and diabetic rats have shown increases in blood glucose and serum insulin. 6

Fertility

Due to its vasodilating properties, forskolin and analogs have been proposed for intercavernosal treatment of erectile dysfunction; however, only small clinical studies have been reported. 44 , 45 An in vitro study demonstrated increased bovine and human sperm motility with forskolin. 46

GI

Animal studies have shown that forskolin promotes gastric and pancreatic acid secretion, as well as relaxes intestinal smooth muscle. 6

Immune

Forskolin has been shown to influence cellular immune responses in vitro and in animal experiments. 6

Ophthalmic

Forskolin has been used in animal and limited clinical studies in glaucoma, with only temporary effects reported. 6

Dosage

Asthma

Oral forskolin has been studied using 10 mg daily over 2 to 6 months. 26 , 27

Obesity

250 mg of a 10% forskolin extract twice daily for 12 weeks has been studied. 24 , 25

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. P. barbatus has been traditionally used as an emmenagogue and oral contraceptive. 2 , 47 Forskolin delayed spontaneous meiotic progression in human oocytes in an in vitro fertility study. 48

Interactions

None reported, but interactions with CYP3A-dependent drugs are theoretically possible. 6 Forskolin exhibits cardiovascular properties and may have additive effects with anticoagulants, antihypertensives, and vasodilators. Potentiation of the antiplatelet effect of prostaglandins and aspirin has been demonstrated in vitro. 6 As a consequence of gluconeogenesis, interference with medicines used in diabetes may be expected. 6

Adverse Reactions

Forskolin-like substances have been identified in renal cyst fluid; therefore, forskolin should be avoided in patients with polycystic kidney disease. 49

Large doses in mice have been reported to have a depressant action on the CNS, and perianal dermatitis has been reported with the use of whole plant extracts. 2 , 6 Clinical trial data are generally lacking; however, a clinical trial found no changes in various metabolic markers or laboratory indices, except for changes in white blood count, serum calcium, ALT, and uric acid levels. 25 Adverse events reported with the use of colforsin (a forskolin derivative) include tachycardia and arrhythmias. 6 , 15

Toxicology

Toxicology information is limited. The oral median lethal dose in rats has been reported to be more than 2,000 mg/kg body weight. 26 The hydroalcoholic extract of the plant has been shown to interfere with embryonic implantation and to delay fetal development. 47

Bibliography

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5. Insel PA, Ostrom RS. Forskolin as a tool for examining adenylyl cyclise expression, regulation, and G protein signaling. Cell Mol Neurobiol . 2003;23(3):305-314.
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11. Siegl AM, Daly JW, Smith JB. Inhibition of aggregation and stimulation of cyclic AMP generation in intact human platelets by the diterpene forskolin. Mol Pharmacol . 1982;21(3):680-687.
12. Adnot S, Desmier M, Ferry N, Hanoune J, Sevenet T. Forskolin (a powerful inhibitor of human platelet aggregation). Biochem Pharmacol . 1982;31(24):4071-4074.
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15. Hayashida N, Chihara S, Tayama E, et al. Antiinflammatory effects of colforsin daropate hydrochloride, a novel water-soluble forskolin derivative. Ann Thorac Surg . 2001;71(6):1931-1938.
16. Suzuki S, Ito O, Sayama T, Yamaguchi S, Goto K, Sasaki T. Intraarterial injection of colforsin daropate hydrochloride for the treatment of vasospasm after aneurysmal subarachnoid hemorrhage: preliminary report of two cases. Neuroradiology . 2006;48(1):50-53.
17. Cohen M, Sklair-Tavron L, Pollack S. The association of forskolin-stimulated cyclic AMP levels in peripheral blood mononuclear cells of healthy people with depressive mood and sense of coherence. Psychophysiol . 2004;18(4):177-183.
18. Gobert D, Topolnik L, Azzi M, et al. Forskolin induction of late-LTP and up-regulation of 5' TOP mRNAs translation via mTOR, ERK, and PI3K in hippocampal pyramidal cells. J Neurochem . 2008;106(3):1160-1174.
19. Seo SR, Kim SS, Chung KC. Activation of adenylate cyclase by forskolin increases the protein stability of RCAN1 (DSCR1 or Adapt78). FEBS Lett. 2009;583(19):3140-3144.
20. Seamon KB, Vaillancourt R, Edwards M, Daly JW. Binding of [3H]forskolin to rat brain membranes. Proc Natl Acad Sci U S A . 1984;81(16):5081-5085.
21. Maeda H, Ozawa H, Saito T, Irie T, Takahata N. Potential antidepressant properties of forskolin and a novel water-soluble forskolin ( NKH477 ) in the forced swimming test. Life Sci . 1997;61(25):2435-2442.
22. Majeed M, et al. Method of preparing a forskolin composition from forskolin extract and use of forskolin for promoting lean body mass and treating mood disorders. 1997; US patent No. 5804596.
23. Okuda H, Morimoto C, Tsujita T. Relationship between cyclic AMP production and lipolysis induced by forskolin in rat fat cells. J Lipid Res . 1992;33(2):225-231.
24. Godard MP, Johnson BA, Richmond SR. Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. Obes Res . 2005;13(8):1335-1343.
25. Henderson S, Magu B, Rasmussen C, et al. Effects of Coleus forskohlii supplementation on body composition and hematological profiles in mildly overweight women. J Int Soc Sports Nutr . 2005;2:54-62.
26. Huerta M, Urzúa Z, Trujillo X, González-Sánchez R, Trujillo-Hernández B. Forskolin compared with beclomethasone for prevention of asthma attacks: a single-blind clinical trial. J Int Med Res . 2010;38(2):661-668.
27. González-Sánchez R, Trujillo X, Trujillo-Hernández B, Vásquez C, Huerta M, Elizalde A. Forskolin versus sodium cromoglycate for prevention of asthma attacks: a single-blinded clinical trial. J Int Med Res . 2006;34(2):200-207.
28. Wajima Z, Yoshikawa T, Ogura A, et al. Intravenous colforsin daropate, a water-soluble forskolin derivative, prevents thiamylal-fentanyl-induced bronchoconstriction in humans. Crit Care Med . 2002;30(4):820-826.
29. Wajima Z, Shiga T, Yoshikawa T, et al. Effect of prophylactic bronchodilator treatment with intravenous colforsin daropate, a water-soluble forskolin derivative, on airway resistance after tracheal intubation. Anesthesiology . 2003;99(1):18-26.
30. Bauer K, Dietersdorder F, Sertl K, Kaik B, Kaik G. Pharmacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma. Clin Pharmacol Ther . 1993;53(1):76-83.
31. Chen J, Hammell DC, Spry M, D'Orazio JA, Stinchcomb AL. In vitro skin diffusion study of pure forskolin versus a forskolin-containing Plectranthus barbatus root extract. J Nat Prod . 2009;72(4):769-771.
32. Lekmine F, Salti GI. Induction of microphthalmia transcription factor (Mitf) by forskolin and stimulation of melanin release in UISO-Mel-6 cells. J Surg Res . 2008;149(1):27-30.
33. Passeron T, Namiki T, Passeron HJ, Le Pape E, Hearing VJ. Forskolin protects keratinocytes from UVB-induced apoptosis and increases DNA repair independent of its effects on melanogenesis. J Invest Dermatol . 2009;129(1):162-166.
34. Watanabe M, Nakajin S. Forskolin up-regulates aromatase (CYP19) activity and gene transcripts in the human adrenocortical carcinoma cell line H295R. J Endocrinol . 2004;180(1):125-133.
35. Watanabe M, Ohno S, Nakajin S. Forskolin and dexamethasone synergistically induce aromatase (CYP19) expression in the human osteoblastic cell line SV-HFO. Eur J Endocrinol . 2005;152(4):619-624.
36. Tong M, Tai HH. Synergistic induction of the nicotinamide adenine dinucleotide-linked 15-hydroxyprostaglandin dehydrogenase by an androgen and interleukin-6 or forskolin in human prostate cancer cells. Endocrinology . 2004;145(5):2141-2147.
37. Li Z, Wang J. A forskolin derivative, FSK88, induces 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. Cell Biol Int . 2006;30(11):940-946.
38. Kim BJ, Kim SS, Kim YI, Paek SH, Lee YD, Suh-Kim H. Forskolin promotes astroglial differentiation of human central neurocytoma cells. Exp Mol Med . 2004;36(1):52-56.
39. Solovjeva LV, Pleskach NM, Firsanov DV, Svetlova MP, Serikov VB, Tomilin NV. Forskolin decreases phosphorylation of histone H2AX in human cells induced by ionizing radiation. Radiat Res . 2009;171(4):419-424.
40. Namkoong S, Kim CK, Cho YL, et al. Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling. Cell Signal . 2009;21(6):906-915.
41. Niu W, Bilan PJ, Hayashi M, Da Y, Yao Z. Insulin sensitivity and inhibition by forskolin, dipyridamole and pentobarbital of glucose transport in three L6 muscle cell lines. Sci China C Life Sci . 2007;50(6):739-747.
42. Richmond SR, Touchberry CD, Gallagher PM. Forskolin attenuates the action of insulin on the Akt-mTOR pathway in human skeletal muscle. Appl Physiol Nutr Metab . 2009;34(5):916-925.
43. Ding WQ, Dong M, Ninova D, Holicky EL, Stegall MD, Miller LJ. Forskolin suppresses insulin gene transcription in islet beta-cells through a protein kinase A-independent pathway. Cell Signal . 2003;15(1):27-35.
44. Drewes SE, George J, Khan F. Recent findings on natural products with erectile-dysfunction activity. Phytochemistry . 2003;62(7):1019-1025.
45. Mulhall JP, Daller M, Traish AM, et al. Intracavernosal forskolin: role in management of vasculogenic impotence resistant to standard 3-agent pharmacotherapy. J Urol . 1997;158(5):1752-1758.
46. Liu JH, Li Y, Cao ZG, Ye ZQ. Influences of dibutyryl cyclic adenosine monophosphate and forskolin on human sperm motility in vitro. Asian J Androl . 2003;5(2):113-115.
47. Almeida FC, Lemonica IP. The toxic effects of Coleus barbatus B . on the different periods of pregnancy in rats. J Ethnopharmacol . 2000;73(1-2):53-60.
48. Shu YM, Zeng HT, Ren Z, et al. Effects of cilostamide and forskolin on the meiotic resumption and embryonic development of immature human oocytes. Hum Reprod . 2008;23(3):504-513.
49. Putnam WC, Swenson SM, Reif GA, Wallace DP, Helmkamp GM Jr, Grantham JJ. Identification of a forskolin-like molecule in human renal cysts. J Am Soc Nephrol . 2007;18(3):934-943.

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