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A Review of the Herbal Phosphodiesterase Inhibitors; Future Perspective of New Drugs Cytokine 49 (2010) 123–129 Contents lists available at ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/issn/10434666 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 appli- cations 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 cardiovas- cular 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 1043-4666/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2009.11.005 124 R. Rahimi et al. / Cytokine 49 (2010) 123–129 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 ÀÀnausea progressively increased [50]. Many pharmacologically active sub- stances that come from plants demonstrate PDEI activity (see Table Selective PDEI1 2). Vinpocetine ÀÀSkin eruption, [27,25] flushing, 2.1.1. Flavonoids PDEI2 The flavonoids are a very large and important group of polyphe- EHNA ÀÀ [28,25] PDEI3 nolic compounds widely distributed in plants [51]. They are plant Enoximone À + 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] ÀÀ [54], anticancer [55], antimutagenic [56], antispasmodic [57], Roliprame À + plasma osmolality Ibudilast ÀÀ(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
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