OJIOpen Journal of Immunology2162-450XScientific Research Publishing10.4236/oji.2016.62006OJI-67619ArticlesMedicine&Healthcare Isoforskolin from Native Plant <i>Coleus forskohlii</i> of Yunnan, China Plays Multiple Biological Roles ShiFeng1LingWang1SupayangP. Voravuthikunchai2ZhangLiang3AihuaLiu4FukaiBao4Department of Microbiology and Immunology, The Institute for Tropical Medicine, Kunming Medical University, Kunming, ChinaYunnan Province Key Laboratory for Tropical Infectious Diseases in Universities, Kunming, ChinaNatural Product Research Center of Excellence, Prince of Songkla University, Songkhla, ThailandYunnan Demonstration Base of International Science and Technology Cooperation for Tropical Diseases, Kunming, China090620160602636611 March 2016accepted 20 June 23 June 2016© Copyright 2014 by authors and Scientific Research Publishing Inc. 2014This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

Isoforskolin (ISOF) was isolated from Coleus forskohlii native to Yunnan in China. It is identified as one analog of diterpene forskolin (FSK) which comes from the Indian plant Coleus forskohlii. Researches found that the Yunnan native plant Coleus forskohlii contained rich ISOF but not FSK. ISOF was reported to activate adenylyl cyclase (AC) isoforms. The ophthalmologic and cardiovascular effects of ISOF were firstly reported in the 1990s. The researchers in Kunming, China, found ISOF could lower blood pressure and intraocular pressure. Recent researches found the respiratory tract effects of ISOF, and showed that ISOF significantly elevated cyclic adenosine monophosphate (cAMP) levels in rat lung homogenate, and relaxed the histamine-induced contraction of isolated guinea pig trachea and lung smooth muscle, isoforskolin pretreatment attenuates acute lung injury induced by lipopolysaccharide (LPS) in several models, lowered LPS-induced secretion of the inflammatory cytokine in human monocytes.

<i>Coleus forskohlii</i> Natural Compound Isoforskolin Bioactivity1. Introduction

Chinese materia medica is popular nationally, as well as being used worldwide. According to recent data from the World Health Organization, the market of Chinese materia medica is substantial. The output of Chinese materia medica was estimated to a more than 20% increase from the past [1] . However, it is still possible that wild plants in China may contain unknown active principles which may be useful drugs and tools for natural sciences and medicine.

A classic example of phytochemicals used extensively in biology and medicine is isoforskolin (ISOF), which is also known as Coleonol B, 6-acetyl-7-deacetyl forskolin, and is isolated from Coleus forskohlii native to Yunnan in China. There are few Chinese medicine’s records of Coleus forskohlii in books of previous dynasties. It was found in the northeast area of Yunnan Province in China in 1989 [2] . ISOF is identified as one analog of diterpene forskolin (FSK) which comes from the Indian plant Coleus forskohlii. Phytochemists found that the Yunnan native plant Coleus forskohlii contained rich ISOF but not FSK [3] . Forskolin (also called coleonol) is labdane diterpene that is produced by the plant Indian Coleus (Coleus forskohlii) from Ayurveda. Forskolin has been commonly used to activate adenylyl cyclase, which provides investigators with a means for researches of the role of cyclic AMP (cAMP) in cell physiology and pathogenesis of several diseases. Recent researches show that ISOF plays multiple biological roles [4] . In this review, we briefly summarize the varied pharmacological effects of ISOF.

2. Pharmacological Actions (<xref ref-type="table" rid="table1">Table 1</xref>)2.1. Ophthalmologic Effects

The Ophthalmologic effects of ISOF were firstly reported in the 1990s [5] , a study of 40 big-eared Japanese rabbits with ISOF administered, indicated that both normal IOP (intraocular pressure) and water-induced OHT (ocular hypertension) were decreased by the ocular hypotensive effect of ISOF when compared with control. Additionally, ISOF suspension at 0.25% exerted little topical irritating actions, which showed the security and reliability of the ocular hypotensive effect of ISOF. With further research on the screened OHT rabbits and water-induced OHT rabbits with ISOF and FSK suspensions respectively at 0.25%, the ocular hypotensive effect of ISOF was more significant than FSK [6] . To study the mechanisms of the ocular hypotensive effect of ISOF, levels of cAMP reflecting AC activity were assayed by protein-binding method of radioimmunoassay in isolated SD rat livers added into the mixture containing isoforskolin and forskolin, respectively. The results demonstrated that isoforskolin and forskolin stimulated adenylate cyclase in vitro with almost equal activity [7] .

On the basis of the above-mentioned animal experiments, a study conducted in 20 healthy Chinese population aged among 23 - 50 years old without eye diseases, investigated the effects of ISOF on the acute increase of intra ocular pressure (IOP) induced by water-drinking (14 ml/kg), showed that ISOF (0.5%) as suspension eye drops also played the ocular hypotensive role [8] .

2.2. Heart-Vascular Effects

The Cardiovascular effects of ISOF were also firstly reported in the 1990s [9] , researchers in Kunming, Yunnan Province of China, found that isoforskolin could reduce blood pressure and benefit heart. Whole platelet aggregation in vitro of 20 Wistar rats induced by adnosine diphosphate (ADP)/arachidonic acid (AA) and 10 guinea pigs induced by platelet activating factor (RAF) was suppressed by ISOF (5, 10 mg/kg).The maximal inhibitory effects appeared at 10 minutes after drug administration, and the inhibitory effects lasted for 2 hours. In view of the inhibition of platelet aggregation and hypotensive effect, ISOF could be used for prevention and treatment of hypertension with platelet aggregation. Furthermore, ISOF could also effectively decrease the blood pressure in anaesthetized rats without influencing the heart rate (HR), electrocardiograph (ECG), left ventricular pressure (LVP), rate of change of left ventricular pressure (LVdp/dt) and left ventricular end diastolic pressure (LVEDP) [10] . Recent study on general pharmacology of ISOF in animal models indicated that ISOF has no significant influence on heart rate, breathing, systolic blood pressure, mean arterial pressure, diastolic blood pressure of SD rats [11] . Thus, the safety of ISOF has been proved through the animal models.

2.3. Respiratory Tract Effects

As ISOF, as an effective AC activator, induces increasing intracellular cAMP, researcher also found that ISOF

The biological effects of ISOF
bioactivitiesdescriptions
ophthalmologic effectsISOF decreasing ocular pressure effect by stimulating adenylate cyclase
heart-vascular effectsISOF show the potentiality for prevention and treatment of hypertension with platelet aggregation
respiratory tract effectsISOF, as an effective AC activator, induces increasing intracellular cAMP, may plays a significant role in immune modulation of inflammatory reaction; ISOF significantly inhibit the contraction of isolated guinea pig trachea induced by histamine diphosphate and acetylcholimium chloride; ISOF pretreatment attenuates acute lung injury induced by lipopolysaccharide (LPS)

plays a significant role in immune modulation of inflammatory reaction, such as mitigating acute lung injury (ALI). ISOF (25, 50, 100 μmol/L) inhibited human polymorphonuclear cell (PMNC) recruitment, expression of PMN adhesion molecules, and TNF-alpha released from PMNC. The effects that ISOF increased the intracellular cAMP might be associated with the mechanism of its mitigating ALI [12] . ISOF was reported to activate adenylyl cyclase (AC) isoforms 1, 2 and 5. The study by Yang et al. demonstrated that ISOF increased cyclic adenosine monophosphate (cAMP) level in rat lung homogenate, and relaxed the histamine-induced contraction of isolated guinea pig trachea and lung smooth muscle. ISOF pretreatment attenuates acute lung injury induced by lipopolysaccharide (LPS). ISOF (50, 100, and 200 µM) and dexamethasone (10 µM) pre-incubation lowered LPS (2 µg/mL)-induced secretion of the cytokine TNF-alpha, and interleukins IL-1 beta, IL-6, and IL-8 In human mononuclear leukocyte. The pretreatment with ISOF attenuates LPS-induced acute lung injury in several models, which is involved in down-regulation of inflammatory responses and proinflammatory cytokines TNF- alpha, IL-1 beta, IL-6, and IL-8 [13] .

Recent research showed that ISOF played the relaxation effects on isolated bronchioles in guinea pig, and significantly inhibited the contraction of isolated guinea pig trachea induced by histamine diphosphate and acetylcholimium chloride [14] .

3. Conclusion

ISOF from plant Coleus forskohlii native to Yunnan Province, which is the main diterpene from the native plant, plays multiple biological roles. The increasing number of new diterpenes isolated from Coleus forskohlii has been reported, and they are definitely worth exploring for further study [15] . The antioxidant activity in tubers of Coleus forskohlii was reported recently, which might protect against oxidant and free radical injures [16] . Coleus forskohlii, which contains multiple bioactive compounds, is a medicinal plant with significant value [17] .

Acknowledgements

This work was supported by National Natural Science Foundation of China grants (No. 81060134, 81371835, 3156005, 81560596); Natural Science Foundation of Yunnan Province grants (2012FB011, 2013FZ057, 2014FA011, 2014FB001).

Cite this paper

Shi Feng,Ling Wang,Supayang P. Voravuthikunchai,Zhang Liang,Aihua Liu,Fukai Bao, (2016) Isoforskolin from Native Plant Coleus forskohlii of Yunnan, China Plays Multiple Biological Roles. Open Journal of Immunology,06,63-66. doi: 10.4236/oji.2016.62006

NOTESReferencesWorld Health Organization (2013) Global Review of T&CM. In WHO Traditional Medicine Strategy: 2014-2023, WHO Press, 20 Avenue Appia, 1211 Geneva 27, Switzerland, 25-26.Yang, S.T. and Gao, F. (2007) Pharmacognostical Studies on Coleus forskohlii Briq. Yunnan University of Traditional Chinese Medicine, 30, 8-10.Xu, L.L. and Kong, L.Y. (2006) Labdane Diterpenoids from Coleus forskohlii (Wild) Briq. Journal of Integrative Plant Biology, 48, 478-481. http://dx.doi.org/10.1111/j.1744-7909.2006.00177.xAlasbahi, R.H. and Melzig, M.F. (2012) Forskolin and Derivatives as Tools for Studying the Role of cAMP. Pharmazie, 67, 5-13.Nie, L.H., Li, X.H., Chen, Z.H., Wang, X.H. and Wang, D.C. (1999) Suppressing Effects of Isoforskolin Administered Topically on Intraocular Pressure in Conscious Rabbits. Chinese Ophthalmology Research, 17, 90-92.Li, X.H., Nie, L.H., Yang, W.M., Chen, Z.H., Wang, X.H. and Luo, L.H. (2000) Suppressing Effect of Isoforskolin and Forskolin on Ocular Hypertension in Rabbits. Chinese Journal of Ophthalmology, 36, 292-294.Yang, W.M., Li, X.H., Chen, Z.H., Nie, L.H., Wang, B.L. and Shen, Z.Q. (2001) Adenylate Cyclase Stimulation and Ocular Hypertension Inhibition by Forskolin Analogs. Chinese Ophthalmology Research, 19, 1-4.Yang, W.M., Li, X.H., Chen, Z.H., Nie, L.H., Li, L. and Lei, W.Y. (2001) Effects of Two Forskolin Analogs on the Elevation of Ocular Pressure in Human. Chinese Journal of Ophthalmology, 19, 556-559.Ma, G.Y., Chen, Z.H. and Wang, D.C. (1994) The Inhibitory Effects of Isoforskolin on Rat and Guinea Pig Platelet Aggregation in the Whole Blood. Journal of Kunming Medical University, 15, 18-21.Chen, B.Y., Lei, X.L., Wang, X.H., Chen, Z.H. and Wang, D.C. (1994) The Effects of 1-Acetylforskolin and Isoforskolin on the Hemodynamics in Rats. Journal of Kunming Medical University, 15, 53-55.Zhao, J.S., Yang, W.M., Yang, Z.B., Li, J.X. and Fu, J.J. (2014) Study on General Pharmacology of Forskolin and Isoforskolin. Journal of Kunming Medical University, 35, 37-40.Pei, X.N., Qing, C., Chen, G.Z., Xu, Y.L., Jin, Q.D., Ma, L.M. and Yang, W.M. (2008) Effects of Active Ingredients from Coleus forskohlii on Human Neutrophil. Chinese Journal of Emergency Medicine, 17, 1266-1270.Yang, W.M., Qiang, D.Q., Zhang, M., Ma, L.M., Zhang, Y.H., Qing, C., Xu, Y.L., Zhen, C.L., Liu, J.K. and Chen, Y.H. (2011) Isoforskolin Pretreatment Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Animal Models. International Immunopharmacology, 11, 683-692. http://dx.doi.org/10.1016/j.intimp.2011.01.011Wang, Y.Q., Cao, S.J., Yin, J.J., Huang, J.M. and Weng, H.B. (2013) Relaxation Effects of Forskolin Analogues on Isolated Bronchioles in Guinea Pig. Chinese Pharmacological Bulletin, 29, 714-717.Shan, Y.S., Xu, L.L, Lu, Y., Wang, X.B., Zheng, Q.T., Kong, L.Y. and Niwa, M. (2008) Diterpenes from Coleus forskohlii (Wild) Briq. (Labiatae). Chinese Pharmacological Bulletin, 56, 52-56. http://dx.doi.org/10.1248/cpb.56.52Khatun, S., Chatterjee, N.C. and Cakilcioglu, U. (2011) Antioxidant Activity of the Medicinal Plant Coleus forskohlii Briq. African Journal of Biotechnology, 10, 2530-2535.Paul, M., Radha, A. and Kumar, D.S. (2013) On the High Value Medicinal Plant, Coleus forskohlii Briq. Hygeia Journal for Drugs & Medicines, 5, 69-78.