Prapapan Temkitthawon

Screening for phosphodiesterase inhibitory activity of Thai medicinal plants

INTRODUCTION Phosphodiesterases (PDEs) are a group of enzymes that have powerful effects on cellular signaling because they regulate the second messenger, cAMP or cGMP. PDE inhibitors have been used for treatment of many indications such as cardiovascular diseases, chronic obstructive pulmonary diseases, erectile dysfunction and pulmonary hypertension. THE AIM OF THE STUDY The aim of the study was to search for sources of PDE inhibitors from Thai biodiversity. MATERIALS AND METHODS Some Thai medicinal plants used as aphrodisiac and neurotonic agents together with plants from Leguminosae collected from the North of Thailand were screened for PDE inhibitory activity using a radioassay. RESULTS Seven from nineteen aphrodisiac and neurotonic plants as well as three from twelve Leguminosae plants showed potent PDEs inhibitory activity. The concentrations that could inhibit 50% PDE activity (IC(50)) of the active extracts were determined in comparison to the standard inhibitor, 3-isobutyl-1-methylxanthine (IBMX). Betula alnoides, Hiptage benghalensis, Leea indica and Senna surrattensis showed IC(50) values in the range of microgram per milliliter while IBMX standard showed an IC(50) value of 0.68+/-0.13 microg/ml. CONCLUSION Thai biodiversity was the great sources of PDE inhibitors.

Kaempferia parviflora, a plant used in traditional medicine to enhance sexual performance contains large amounts of low affinity PDE5 inhibitors

AIM OF THE STUDY A number of medicinal plants are used in traditional medicine to treat erectile dysfunction. Since cyclic nucleotide PDEs inhibitors underlie several current treatments for this condition, we sought to show whether these plants might contain substantial amounts of PDE5 inhibitors. MATERIALS AND METHODS Forty one plant extracts and eight 7-methoxyflavones from Kaempferia parviflora Wall. ex Baker were screened for PDE5 and PDE6 inhibitory activities using the two-step radioactive assay. The PDE5 and PDE6 were prepared from mice lung and chicken retinas, respectively. All plant extracts were tested at 50 μg/ml whereas the pure compounds were tested at 10 μM. RESULTS From forty one plant extracts tested, four showed the PDE5 inhibitory effect. The chemical constituents isolated from rhizomes of Kaempferia parviflora were further investigated on inhibitory activity against PDE5 and PDE6. The results showed that 7-methoxyflavones from this plant showed inhibition toward both enzymes. The most potent PDE5 inhibitor was 5,7-dimethoxyflavone (IC(50) = 10.64 ± 2.09 μM, selectivity on PDE5 over PDE6 = 3.71). Structure activity relationship showed that the methoxyl group at C-5 position of 7-methoxyflavones was necessary for PDE5 inhibition. CONCLUSIONS Kaempferia parviflora rhizome extract and its 7-methoxyflavone constituents had moderate inhibitory activity against PDE5. This finding provides an explanation for enhancing sexual performance in the traditional use of Kaempferia parviflora. Moreover, 5,7-dimethoxyflavones should make a useful lead compound to further develop clinically efficacious PDE5 inhibitors.

Curcumin analogues inhibit phosphodiesterase‐5 and dilate rat pulmonary arteries

Phosphodiesterase (PDE)‐5 inhibitors are useful as vasodilators for the treatment of pulmonary arterial hypertension. We aimed to study curcumin analogues for PDE5 inhibitory activity and vasorelaxation of rat pulmonary arteries.

Effect of Curcumin and Its Analogs on Rat Pulmonary Artery

Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok 65000, Thailand; Department of Physiology, Faculty of Medical Sciences, Naresuan University, Phitsanulok 65000, Thailand; Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Sciences, Ramkhamhaeng University, Bangkok 10240, Thailand; Division of Physical science, Faculty of Science and Technology, Huachiew Chalermprakiet University, .Samutprakarn 10540, Thailand; E-mail: Kratai-taibio@hotmail.com

Vasorelaxant and hypotensive effects of an ethanolic extract of Eulophia macrobulbon and its main compound (1-(4'-hydroxybenzyl)-4,8-dimethoxyphenanthrene-2,7-diol)

Background: Ethnopharmacological studies demonstrated the potential for Eulophia species to treat inflammation, cancer, and cardio-metabolic diseases. The aim of the study was to investigate the vasorelaxant effect of ethanolic Eulophia macrobulbon (EM) extract and its main phenanthrene on rat isolated mesenteric artery and to investigate the hypotensive effect of EM. Methods: The vasorelaxant effects of EM extract or phenanthrene and the underlying mechanisms were evaluated on second-order mesenteric arteries from Sprague Dawley rats. In addition, the acute hypotensive effect was evaluated in anesthetized rats infused with cumulative concentrations of the EM extract. Results: Both EM extract (10-4–1 mg/ml) and phenanthrene (10-7–10-4 M) relaxed endothelium-intact arteries, an effect that was partly reduced by endothelium removal (p < 0.001). A significant decrease in the relaxant effect of the extract and the phenanthrene was observed with L-NAME and apamin/charybdotoxin in endothelium-intact vessels, and with iberiotoxin in denuded vessels. SNP (sodium nitroprusside)-induced relaxation was significantly enhanced by EM extract and phenanthrene. By contrast, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one), 4-aminopyridine and glibenclamide (endothelium-denuded vessels) and indomethacin (endothelium-intact vessels) had no effect. In calcium-free solution, both the EM extract and phenanthrene inhibited extracellular Ca2+-induced contraction in high KCl and phenylephrine (PE) pre-contracted rings. They also inhibited the intracellular Ca2+ release sensitive to PE. The acute infusion of EM extract (20 and 70 mg/kg) induced an immediate and transient dose-dependent hypotensive effect. Conclusion: The ethanolic extract of EM tubers and its main active compound, 1-(4′-hydroxybenzyl)-4,8-dimethoxyphenanthrene-2,7-diol (phenanthrene) induced vasorelaxant effects on rat resistance vessels, through pleiotropic effects including endothelium-dependent effects (NOS activation, enhanced EDH production) and endothelium-independent effects (opening of KCa channels, inhibition of Ca2+ channels, inhibition of intracellular Ca2+ release and PDE inhibition).

Curcumin Analogues as Lead for PDE5 Inhibitors

Erectile Dysfunction (ED) is a common public health problem affecting millions of men worldwide. Phosphodiesterase 5 (PDE5) inhibitors can be used for the treatment of ED. However, most of PDE5 inhibitors show some undesirable side effects. The aim of the study is to search for new PDE5 inhibitors from synthesis and natural sources. In our preliminary screening, we found that curcumin, a major component in Curcuma longa L., together with its analogues showed inhibition effect on PDE5. Interestingly, some analogs showed no effect on PDE6 which is the isozyme that can be found in rod and cone cells within the eye. The IC50 value of curcumin analogue, ASKI087 against PDE5 was in a micromolar range. The curcuminoid structure could be a promising lead for PDE5 inhibitors.

wall. Ex Baker: A Source of PDE5 Inhibitors

Department of Pharmaceutical Chemistry and Pharmacognosy and Center of Excellence for Innovation in Chemistry, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand; Department of Pharmacology, University of Washington, Seattle, USA; Department of Pharmaceutical Technology and Center of Excellence for Innovation in Chemistry, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand; Center for Bioactive Natural Products from Marine Organisms and Endophytic Fungi, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; Department of Chemistry, Faculty of Sciences, Chulalongkorn University, Bangkok 10330, Thailand; E-mail: prapapantem@gmail.com