A Review of the Herbal Phosphodiesterase Inhibitors; Future Perspective of New Drugs

Cytokine 49 (2010) 123–129

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Cytokine

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Review Article A review of the herbal phosphodiesterase inhibitors; Future perspective of new drugs

Roja Rahimi a, Sima Ghiasi b, Hanieh Azimi b, Sima Fakhari b, Mohammad Abdollahi b,* a Faculty of Traditional Medicine, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran 1417614411, Iran b Faculty of Pharmacy, and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences (TUMS), Tehran 1417614411, Iran article info abstract

Article history: Phosphodiesterase inhibitors (PDEIs) are a class of drugs that are widely used because of their various Received 20 July 2009 pharmacological properties including cardiotonic, vasodilator, smooth muscle relaxant, antidepressant, Received in revised form 17 September antithrombotic, bronchodilator, antiinflammatory and enhancer of cognitive function. In the recent years, 2009 interest in drugs of plant origin has been progressively increased. Some pharmacologically active sub- Accepted 5 November 2009 stances that come from plants demonstrate PDEI activity. They mainly belong to alkaloids, flavonoids, and saponins. In this review, studies on herbal PDEI were reviewed and their possible therapeutic applications were discussed. Screening plants for PDE inhibitory activity may help to develop standardized Keywords: phytotherapeutic products or find new sources for new lead structures with PDEI pharmacological activ- Phosphodiesterase inhibitors Natural ity. The studies discussed in this paper are mainly in vitro and for more reasonable and conclusive results, cGMP it is required to conduct in vivo and finally human and clinical tests. cAMP Ó 2009 Elsevier Ltd. All rights reserved.

1. Phosphodiesterases (PDEs)1 tory, antioxidant [12–15] and enhancer of cognitive function such as learning and memory based on type of PDE inhibiting [16–18]. PDEs are a class of enzymes that are able to cleave the phosphodi- By these actions PDEIs can be used as therapeutic agents for vari- ester bond in either cyclic adenosin monophosphate (cAMP) or cyclic ous diseases such as dementia, depression, schizophrenia [19], guanosine monophosphate (cGMP) to yield 50-cyclic nucleotides. congestive heart failure [20,21], asthma, chronic obstructive pul- Thus they are responsible for controlling cellular concentration of monary disease, diabetes [12], rheumatoid arthritis, multiple scle- cAMP and cGMP by hydrolyzing them to 50-AMP and 50-GMP [1,2]. rosis, Crohn’s disease [22], erectile dysfunction in men [23], and The human genome encode 21 PDE genes that are categorized persistent pulmonary hypertension of the newborn [24]. into 11 families [1] based on protein sequence, structure, substrate The PDEIs can be broadly divided into two groups: (1) standard specificity, enzymatic properties, sensitivity to selective inhibitors, non-selective inhibitors of PDE activity and (2) inhibitors that are and tissue distribution [3–6]. Some PDEs are highly specific for selective for individual PDE isoenzymes (see Table 1) [25–32]. cAMP (PDE4, PDE7, PDE8); some are highly specific for cGMP PDE1 includes numerous isoforms [33]. Some PDEI isoforms have (PDE5, PDE6, PDE9), and others have mixed specificity (PDE1, higher affinity for cGMP than for cAMP whereas some have higher PDE2, PDE3, PDE10, PDE11) [7,8]. Genes of PDE family are affinity for cAMP [34]. PDE1 isozymes are present in the central expressed in nearly all tissues and thus this class of enzymes influ- nervous system, heart, kidney, lung, and smooth muscle ence many physiological functions such as cardiac contractility, [2,35,36]. PDE1 inhibitors are possible therapeutic targets in smooth muscle relaxation, platelet aggregation, visual response, dementia and memory loss [35,36]. Both cAMP and cGMP are sub- fluid homeostasis, and immune responses [9–11]. strates for PDE2 [6]. PDE2 is expressed in adrenal gland, heart, lung, liver, and platelets. Disease targets for PDE2 inhibitors are 2. Phosphodiesterase inhibitors (PDEIs) sepsis and acute respiratory distress syndrome. The only known selective inhibitor of PDE2 is erythro-9-(2-hydroxyl-3-nonyl)-ade- Inhibitors of PDEs have demonstrated various pharmacological nine (EHNA) [2,28,37]. PDE3 has higher affinity for cAMP than properties including cardiotonic, vasodilator, smooth muscle relax- cGMP. It is mainly expressed in the vasculature, the airways, liver, ant, antidepressant, antithrombotic, bronchodilator, antiinflamma- platelets, adipose tissue, and inflammatory cells. PDE3 inhibitors have been identified as a potential therapeutic target in cardiovascular disease and asthma and inhibit platelet aggregation and in- * Corresponding author. Tel./fax: +98 216 6959104. duce lipolysis. PDE4, a cAMP PDE, is the predominant isoenzyme E-mail address: [email protected] (M. Abdollahi). 1 Abbreviations: PDE, phosphodiesterase; PDEI, phosphodiesterase inhibitor; cAMP, in the majority of inflammatory cells. It is expressed in the airways cyclic adenosin monophosphate; cGMP, cyclic guanosine monophosphate. smooth muscle, brain, cardiovascular tissues, and kidney so its

Table 1 strate PDE, acting on both cAMP and cGMP. There is evidence for Classification of FDA-approved phosphodiesterase inhibitors. PDE11 expression in skeletal muscle, prostate, testis and salivary Example FDA- EMEA- Most common Reference glands. The function of PDE11 remains largely unknown, but grow- drugs approved approved side effects ing evidence points to a possible role in male reproduction [49]. therapeutic therapeutic application application 2.1. Natural PDEIs Non-selective Theophylline + + Cardiac [25,26] Over the last decade, interest in drugs of plant origin has been Caffeine + + dysrithmias, IBMX nausea progressively increased [50]. Many pharmacologically active substances that come from plants demonstrate PDEI activity (see Table Selective PDEI1 2). Vinpocetine Skin eruption, [27,25] flushing, 2.1.1. Flavonoids PDEI2 The flavonoids are a very large and important group of polyphe- EHNA [28,25] PDEI3 nolic compounds widely distributed in plants [51]. They are plant Enoximone + Cardiovascular [26,25] phytochemicals that cannot be synthesized by humans [52]. Flavo- Milrinone + + noids are reported to have therapeutic potential because of their PDEI4 antioxidant [53] antiinflammatory, antihepatotoxic, antiulcer Mesembrine Nausea, vomiting, [25,26,29,30] [54], anticancer [55], antimutagenic [56], antispasmodic [57], Roliprame + plasma osmolality Ibudilast (rolipram), anti-allergic, antiviral [58] activities and protection against cardio- dyspepsia vascular mortality [58–60]. Flavonoids have been reported to inhi- PDEI5 bit xanthine oxidase [61], protein kinase C [62] and PDE [63]. Sildenafil + + Headache, [31,32,25] Various flavonoids isolated from different plant species have Tadalafil + + flushing, dyspepsia Vardenafil + + shown inhibitory effect on several isoforms of PDE. Nikaido et al. [64] focused on medicinal plants containing flavonoids i.e. Sophora IBMX: isobutylmethylxanthine; EHNA: erythro-9-(2-hydroxy-3-nonyl)adenine; spp., Scutellaria spp., Rheeoia sp. and Euchresta japonica and demon- EMEA: an EU regulatory agency for evaluation of medicinal products; FDA: Food and Drug Administration. strated that flavanones present in their aqueous extracts have cAMP PDE inhibitors. Orallo et al. [65] showed that (±)naringenin as a natural flavonoid isolated from citrus fruits characterized as an agent with clear vasorelaxant effects on rat aortic smooth mus- disease targets are allergic rhinitis, psoriasis, multiple sclerosis, cle probably mediated by an increase in systolic cAMP and cGMP depression, Alzheimer’s disease, schizophrenia, memory loss, can- concentrations. They reported PDE1, 4, and 5 inhibitory activities cer, and dermatitis [10]. PDE5, a cGMP-specific PDE, is expressed in for this compound. Ning et al. [66] isolated icariin as a flavonoid lung, platelets, and vascular smooth muscle. PDE5 inhibitors are from Epimedii herba and reported that icariin inhibits PDE5 isoform able to induce vascular smooth muscle relaxation. Therefore and is more effective than zaprinast, as a standard PDE5 inhibitory PDE5 inhibitors are possible therapeutic targets in cardiovascular drug, in maintaining greater cGMP level. Nagai et al. [67] reported disease, pulmonary hypertension, female sexual dysfunction, pre- that licochalcone A, as a flavonoid, is responsible for the relaxant mature ejaculation, stroke, leukemia, and renal failure [4,38,39]. activity of Glycyrrhiza inflanta root and this action is supposed to PDE6 is highly concentrated in the retina. It is most abundant in be mediated by inhibition of cAMP PDE. Liu et al. [68] showed isoli- the internal membranes of retinal photoreceptors, where it reduces quiritigenin, a flavonoid in Glycyrrhiza glabra, has PDEI effect. Ko cytoplasmic levels of cGMP in rod and cone outer segments in re- et al. [69] reported PDEI activity from 3-O-methylquercetin in sponse to light having an essential role in visual function. Since the Rhamnus nakaharai. Shin et al. [70] demonstrated that sophoflav- catalytic sites of PDE5 and PDE6 is similar with respect to drug esenol, a flavanone in Sophora flavescens has PDEI effect. Lines binding, most PDE5 inhibitors inhibit PDE6 with similar potency and Ono [71] showed that quercetine in Allium cepa has PDE5 and thus cause visual disturbances [40]. PDE7 is a cAMP-specific inhibitory effect. Sánchez-Mendoza et al. [72] reported probably PDE expressed widely in immune and pro-inflammatory cells. flavonoids in Gnaphalium liebmanni has PDE inhibitory effect. Del- Drugs inhibiting PDE7 have potential to be proposed as novel anti- l’Agli et al. [73] isolated anthocyanin from Vitis vinifera and showed inflammatory drugs. Up to now, there is no approved selective anthocyanin inhibits PDE5. inhibitor of PDE7. Some examples of compound with acceptable Other plants that have shown PDEI activity because of their fla- selective PDE7 inhibitory activity for in vitro studies are benzo- vonoid contents are Berchemia floribunda, Betula alnoids, Boesenbe- and benzothienothiadiazine dioxides, sulfonamide derivatives, riga rotunda, Caesalpinia sappan, Hiptage benghalensis, Leea indica, and guanine analogs [41–45]. PDE8 is a family of cAMP-specific en- Ventilago denticulate, Bauhinia winitii, Butea monosperma, Senna zymes and plays important roles in many biological processes, surattensi [74], Matricaria recutita [57], Decussocarpus rospigliosii including T-cell activation, testosterone production, adrenocortical [75], Crataegus oxyacantha [76], Butea superba [77], Desmodium tri- hyperplasia, and thyroid function. However, no PDE8 selective quetrum [78], Eleutherococcus senticosus, Plantago asiatica, Plantago inhibitors are available for trial treatment of human diseases major [79], and Ginkgo biloba [80]. [46]. PDE9 is highly specific for cGMP and its high expression has been detected in various tissues, including brain, kidney, spleen, 2.1.2. Alkaloids prostate, colon, and intestine. BAY 73-6691 is a novel potent and The alkaloids are natural nitrogen-containing secondary metab- selective PDE9 inhibitor that is under preclinical development for olites mostly derived from amino acids and found in about 20% of the treatment of Alzheimer’s disease [47]. PDE10 shows a dual plants [81]. Present of alkaloids is not limited to just plants but also activity on hydrolysis of both cAMP and cGMP and is highly ex- exist in marine organism, insects, microorganism and some ani- pressed in brain striatum. The PDE10 inhibitor, papaverine, is mals such as frogs, and some reptiles [82]. A number of plant alka- effective in improving executive function deficits associated with loids show inhibitory effect on PDE. Ohmoto et al. [83] reported schizophrenia, and therefore inhibition of PDE10 may represent that Picrasma quassiodes and Ailanthus altissima have inhibitory an approach to treatment of psychosis [48]. PDE11A is a dual-sub- effect on cAMP PDEs because of their alkaloids. Chen et al. [84] Table 2 Plants with phosphodiesterase inhibitory activity.

Plant Family Type of extract Part of Effective material Experimental method Effect Reference plant Berchemia floribunda Rhamnaceae Ethanol Stem Flavonoids In vitro PDEI [74] Betula alnoids Betulaceae Ethanol Stem bark Flavonoids In vitro PDEI Boesenberiga rotunda Zingiberaceae Ethanol Rhizome Flavonoids In vitro PDEI Caesalpinia sappan Fabaceae Ethanol Stem Flavonoids In vitro PDEI Hiptage benghalensis Malpighiaceae Ethanol Stem Flavonoids In vitro PDEI Leea indica Leeaceae Ethanol Root Flavonoids In vitro PDEI Ventilago denticulata Rhamnaceae Ethanol Stem Flavonoids In vitro PDEI Bauhinia winitii Fabaceae Ethanol Leaf Flavonoids In vitro PDEI Butea monosperma Fabaceae Ethanol Leaf Flavonoids In vitro PDEI Senna surattensis Fabaceae Ethanol Leaf Flavonoids In vitro PDEI Nelumbo nucifera Nelumbonaceae Purchased NEF 98% Green Neferin (bis-benzylisoquinoline Male New Zealand white rabbit cAMP and cGMP [85] seed alkaloid) corpus cavernosum PDE(1,2,3,4,7,8,10)I embryo Matricaria recutita L. Asteraceae Infusions ofsifted flowers with Flowers Flavonoids Nucleotidase from Crotalus Sspasmolytic (cAMP PDEI) [75] deionized water adamanteus snake venom and human platelet cAMP PDE Glycyrrhiza glabra Fabaceae Ethyl acetate Roots Isoliquiritigenin, flavonoids Guinea-pig tracheal smooth muscle Relaxing effect [68]

(in vitro and in vivo) 123–129 (2010) 49 Cytokine / al. et Rahimi R. Decussocarpus rospigliosii Podocarpaceae Ethyl acetate Leaves Biflavones PDE isoforms from bovine aortic PDEI [76] smooth muscle and human platelet Crataegus oxyacantha Rosaceae Leaves and Bioflavonoids: quercetin, Guinea pigs PDEI [77] flower hyperoside, rutin, flavonoglycosyls, 0 vitexin-4 -rhamnoside Glycyrrhiza inflanta Fabaceae Water Root Licochalcone A Jejunum of male ICR mouse Antispasmodic (cAMP PDEI) [67] Allium cepa Liliaceae FRS 1000 (a beverage Red onion Quercetin SPA PDE enzyme assay PDE5I [71] containing flavonoids peel extracted from onion peel) Glycyrrhiza ularensis Fabaceae Water–methanol Root Glycocoumarin Mouse jejunum A potent antispasmodic [105] (PDE3I) Epimedii herba Berberidaceae Ethanol Aerial part Icariin Rat cavernous smooth muscle cell PDE5A1-A2-A3I [66] Gnaphalium liebmanni Asteraceae Hexane, dichloromethane, and Aerial part Probably flavonoids Guinea-pig tracheal smooth muscle PDEIr [72] methanol Viscum coloratum Loranthaceae Methanol Stem Viscolin Human neutrophil superoxide anion cAMP PDEI [86] and elastase Citrus fruits Rutaceae Purchased naringenin Fruit (±)-naringenin (flavanone) Bovine aorta PDE1, 4, 5I [65] Vitis vinifera Vitaceae Grape skin Anthocyanin Smooth muscle (in vitro) PDE5I [73] Baccharis trimera (Less.) De Asteraceae Dichloromethane, methanol, Aerial Diterpenes, saponins, flavonoids Male albino and guinea pigs Relaxant effect on the [108] candolle aqueous parts smooth muscle of corpus cavernosum (PDEI) Haplopappus rigidus phil. Asteraceae Dichloromethane, methanol, Aerial Essential oils, resins; diterpenes Male albino and guinea pigs Relaxant effect on the aqueous parts smooth muscle of corpus cavernosum (PDEI) Huperzia saururus Lycopodiaceae Dichloromethane, methanol, Leaves Alkaloids Male albino guinea pigs (in vitro) Relaxant effect on the aqueous smooth muscle of corpus cavernosum (PDEI) Maytenus ilicifolia Mart. ex Celastraceae Dichloromethane, methanol, Aerial Alkaloids, terpene Male albino guinea pigs (smooth PDEI reisseck aqueous parts muscle of corpus cavernosum) (in vitro) Satureja parviflora (phil.) Epling Lamiaceae Dichloromethane, methanol, Leaves Essential oils, flavonoids Male albino guinea pigs (smooth PDEI aqueous muscle of corpus cavernosum) (in vitro) Senecio eriophyton Asteraceae Dichloromethane, methanol, Aerial Essential oils, resins, sesquiterpenes Male albino guinea pigs (smooth PDEI J. Remi aqueous parts muscle of corpus cavernosum) (in vitro) 125 (continued on next page) 126 Table 2 (continued)

Plant Family Type of extract Part of Effective material Experimental method Effect Reference plant Butea superba Fabaceae – Tuber Flavonoid, Flavonoid glycoside Human (double-blind clinical trial cAMP PDEI [78] Rhamnus nakaharai Rhamnaceae 3- O-Methylquercetin collected Stem bark 3- O-Methylquercetin PDE isozymes from guinea pigs’ Selective and competitive [69] lungs and hearts PDE3I and PDE4I Sophora flavescens Lamiaceae Methanol Root Sophoflavesenol (c8-prenylated Rat’s diaphragm cGMP PDE5I [70] flavanone) Desmodium triquetrum D.C. Papilionaceae Ethanol Leaf Flavonoids, alkaloids In vitro PDEI [79] Allium chinense Liliaceae Ethanol Bulb Steroidal saponins In vitro cAMP PDEI [98] Cnidium monnier (L.) cusson Apiaceae Ethanol Fruit Osthole (coumarin) Rabbit’s corpus cavernosum PDE5I; release of NO from [106] sinusoidal endothelium Angelica pubescens Apiaceae – Dried root Osthole (coumarin) Guinea pig’s tracheal smooth muscle cAMP and cGMP PDEI [107] Plantago asiatica and P. major Plantaginaceae – – Plantamajoside, hellicoside, Beef’s heart cAMP PDE cAMP PDEI [80] plantaginin Plantago asiatica and P. major Plantaginaceae – – Plantaginin Guinea pigs cAMP PDEI, anti-allergic effect Eleutherococcus senticosus Araliaceae – – (+)-Syringaresinol di- O-b-D- In vitro cAMP PDEI (Rupr. et Maxim) Maxim glucoside (Siberian geinseng) Lilium regale and L. henryi Liliaceae – Bulb Steroidal saponins In vitro cAMP PDEI [97]

Periandra dulcis Mart Leguminosae MeOH Roots Saponins (periandradulcins A,B,C) PDE from bovine heart PDE1 inhibitor [99] 123–129 (2010) 49 Cytokine / al. et Rahimi R. Euchresta japonica Fabaceae Aqueous – Flavanone Beef heart cAMP PDEI [64] Rheeoia sp. Euphorbiaceae Aqueous – Flavanone Beef heart cAMP PDEI Scutellaria baicalensis Lamiaceae Aqueous – Flavanone Beef heart cAMP PDEI Scutellaria discolor Lamiaceae Aqueous – Flavanone Beef heart cAMP PDEI Sophora flavescens Lamiaceae Aqueous – Flavanone Beef heart cAMP PDEI Scutellaria indica Lamiaceae Aqueous – Flavanone Beef heart cAMP PDEI Scutellaria scandens Fabaceae Aqueous – Flavanone Beef heart cAMP PDEI Sophora tomentosapre Fabaceae Aqueous – Flavanone Beef heart (in vitro) cAMP PDEI Picrasma quassiodes Simarubaceae Aqueous – Alkaloids Beef heart PDE cAMP PDEI [84] Ailanthus altissima Simarubaceae Aqueous – Alkaloids Beef heart PDE (in vitro) cAMP PDEI Eucommia ulmoides Ecommiaceae Aqueous Bark Lignan glucosides Beef heart PDE (in vitro) cAMP PDEI [101] Ginkgo biloba Ginkgoaceae – Leaves Flavones glycoside Brain of normal and triethyltin in rats cAMP PDEI [81] Iris florentina Iridaceae Aqueous Rhizome Norlignan Beef heart PDE cAMP PDEI [102] Polygala tenuifolia Polygalaceae Aqueous Radix Norlignan Beef heart PDE cAMP PDEI Glycyrrhiza glabra var. Fabaceae Aqueous Radix Norlignan Beef heart PDE cAMP PDEI glandulifera Nepeta japonica Lamiaceae Aqueous Herb Norlignan Beef heart PDE cAMP PDEI Cassia obtusifolia Fabaceae Aqueous Seed Norlignan Beef heart PDE cAMP PDEI Daphne genkwa Thymelaeaceae Aqueous Flower- Norlignan Beef heart PDE cAMP PDEI bud Carthamus tinctorius Asteraceae Aqueous Flower Norlignan Beef heart PDE cAMP PDEI Bupleurum facatum Apiaceae Aqueous Radix Norlignan Beef heart PDE cAMP PDEI Asiasarum sieboldi Aristolochiaceae Aqueous Radix Norlignan Beef heart PDE cAMP PDEI Zanthoxylum piperitum Rutaceae Aqueous Fruit Norlignan Beef heart PDE cAMP PDEI Fraxinus bungeann Oleaceae Aqueous Bulk Norlignan Beef heart PDE cAMP PDEI Citrus reticulate Rutaceae Aqueous Immature- Norlignan Beef heart PDE cAMP PDEI peel Nuphar japonicum Nelumbiaceae Aqueous Radix Norlignan Beef heart PDE cAMP PDEI Inula britannica Asteraceae Aqueous Flower Norlignan Beef heart PDE cAMP PDEI Amomum costatum Zingiberaceae Aqueous Fruit Norlignan Beef heart PDE cAMP PDEI Lamiaceae Aqueous Herb Norlignan Beef heart PDE cAMP PDEI Areca catechu Arecaceae Aqueous Peel Norlignan Beef heart PDE cAMP PDEI Aralia elata Araliaceae Aqueous Root-bulk Norlignan Beef heart PDE cAMP PDEI Phyllostachys nagra Poaceae Aqueous Cortex Norlignan Beef heart PDE cAMP PDEI Anemarrhena asphodeloides Agavaceae Aqueous Rhizome Norlignan Beef heart PDE cAMP PDEI Caesalpinia sappan Fabaceae Aqueous Wood Norlignan Beef heart PDE cAMP PDEI Forsythia suspensa Oleaceae Aqueous Fruit Norlignan Beef heart PDE cAMP PDEI R. Rahimi et al. / Cytokine 49 (2010) 123–129 127 isolated neferin, a bis-benzyl isoquinoline alkaloid, from Nelumbo Chen et al. showed that neferin in N. nucifera inhibits PDE1, 2, 3, nucifera and showed that neferin enhances the concentration of 4, 7, 8, and 10 [84]; thus PDEI action of this plant is not selective. cAMP in rabbit cavernosum tissue probably by inhibiting PDE Quercetin in red onion peel [71], icariin in E. herba [66], sophoflav- activity. Hwang et al. [85] reported viscolin in Viscum coloratum esenol in S. flavescens [70], osthole in C. monnier [105], and antho- has PDE inhibitory effect. cyanin in V. vinifera [73] have been shown to inhibit PDE5; hence they are possible therapeutic candidate in cardiovascular diseases, 2.1.3. Saponins pulmonary hypertension, female sexual dysfunction, premature Saponins are a group of glycosides generally known as non-vol- ejaculation, stroke, leukemia, and renal failure. Naringenin in Cit- atile, surface active compounds including steroids, steroidal alka- rus fruits has inhibited PDE1, 4, and 5 [65] and thus it is suggested loids, and triterpenoids as aglycones that are widely distributed as a therapeutic target for memory loss and dementia, allergic and in nature, occurring primarily in the plants kingdom [86,87]. Sap- autoimmune disorders, cardiovascular disease, and renal failure. 3- onins have a diverse range of properties, including hemolytic prop- O-Methylquercetin in R. nakaharai has inhibited PDE3, and 4 [69]. erties [88], as well as hepatoprotective, antimutagenic, antiviral, Since both of these enzymes are expressed in inflammatory cells, antileishmanial and antiinflammatory activities [89–95]. Some it is suggested to have immunomodulatory properties and is pro- plants have demonstrated PDEI activity related to their saponin posed as an effective medication for allergic and autoimmune dis- content. Mimaki et al. [96] reported that Lilium regale and Lilium eases. Glycocoumarins in the root of G. ularensis have shown PDE3 henryi have inhibitory effects on cAMP PDE. The main active sub- inhibitory activity [104]; thus they may have potential as thera- stances present in these plants are steroidal saponins. Kuroda peutic targets for cardiovascular disease, asthma, and obesity. et al. [97] showed that ethanol extract of Allium chinense has inhib- Non-selective PDEIs including theophylline and papaverine itory activity on cAMP PDE, probably because of its saponin con- have been used therapeutically for over 70 years. However, it is tent. Ikeda et al. [98] showed saponins in Periandra dulcis have only in the last 10 years that potent PDE selective drugs e.g. vinp- PDE inhibitory activity especially for PDE1. ocetine, EHNA, enoximone, ibudilast, and sildenafil have been used to treat diseases. These selective PDEIs have less adverse events 2.1.4. Lignans than non-selective ones [25–32]. One of interesting potentials of Lignans are dimeric compounds formed essentially by the union PDEIs is their antioxidant effects that can interact with free radicals of two molecules of a phenylpropene derivative [99]. Deyama et al. that are involved in pathogenesis of some important human dis- [100] showed lignans in Eucommia ulmoides have PDEI effect. Nika- ease and hopefully some herbal products have been found useful ido et al. [101] reported PDEI activity from norlignans of Iris floren- for these purposes in the recent years [108–116]. Over the past tina, Polygala tenuifolia, G. glabra var. glandulifera, Nepeta japonica, decade, interest in drugs derived from plants increased expres- Cassia obtusifolia, Daphne genkwa, Carthamus tinctorius, Bupleurum sively. These drugs may be standardized herbal preparations con- facatum, Asiasarum sieboldi, Zanthoxylum piperitum, Fraxinus bunge- sisting of complex mixtures of one or more plants called ann, Citrus reticulate, Nuphar japonicum, Inula britannica, Amomum phytomedicines or chemical compounds derived from plants. It is costatum, Perilla frutescens, Areca catechu, Aralia elata, Phyllostachys estimated that about 25% of all modern medicines are directly or nagra, Anemarrhena asphodeloides, C. sappan and Forsythia suspense. indirectly derived from plants. Several important factors contribut- ing to the growth of phytomedicine market are preference and great interest of consumers for natural therapies. Herbal drugs 2.1.5. Coumarins are believed to have undesirable side effects of modern medicines The coumarins are benzopyrone derivative compounds with and are free from side effects because of people all over the world various pharmacological and biochemical properties and therapeu- have been using herbal medicines for thousands of years. Compar- tic applications depending on the pattern of substitution. Some of ing herbal medicines to conventional therapies and medicines, their pharmacological activities are reduction of lymphoedema, there are serious concerns about efficacy and sometimes safety hypolipidaemic, antioxidant, hypotensive, inhibition of platelet of herbal medicines whereas phytomedicines have lower cost in aggregation, antispasmodic properties antitumoural, anti-HIV and comparison to synthetic medicines [117]. as CNS-active compounds [102,103]. Sato et al. [104] reported po- Screening plants for PDE inhibitory activity may help to develop tent antispasmodic properties from glycocoumarins in the root of standardized phytotherapeutic products or find new sources for Glycyrrhiza ularensis mediated by PDE3 inhibitory activity. Osthole, new lead structures with PDEI pharmacological activity. The stud- a coumarin isolated from Crindium monnier and Angelica pubescens ies discussed in this paper are mainly in vitro and for more reason- has shown PDE inhibitory activity [105,106]. able and conclusive results, it is required to do in vivo and finally human and clinical tests. 2.1.6. Essential oils Essential oils, as their name implies, are volatile in steam. They differ entirely in both chemical and physical properties from fixed Acknowledgment oils. They are secreted in oil cells, in secretion ducts or cavities or in glandular hairs. They are found in plants belonged to different fam- This review is the outcome of an in-house independent research ilies especially Lamiaceae. Different pharmacological properties and has not been supported by any source of funds. have been reported from essential oils mainly antimicrobial, car- minative, and antispasmodic activities [99]. Hnatyszyn et al. [107] showed that essential oils and resins in Haplopappus rigidus, References Satureja parviflora and Senecio eriophyton have PDEI activity. [1] Omori K, Kotera J. Overview of PDEs and their regulation. Circ Res 3. Discussion 2007;100:309–27. [2] Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 2006;58:488–520. In this paper, all studies on plants with PDEI activity published [3] Kotera J, Sasaki T, Omori K. Recent progress in cyclic nucleotide without date limitation were collected and explained. 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