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the roots of Sophora flavescens Aiton (Fabaceae), both of which were more effective against MAO-B rather than MAO-A (Table 1). [34]. On the other hand, ...
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268

Potential of Natural Products of Herbal Origin as Monoamine Oxidase Inhibitors Ilkay Erdogan Orhan* Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey Abstract: Monoamine oxidase (MAO, E.C. 1.4.3.4) is a flavin-adenine type of enzyme with two isoforms referred to MAO-A and MAO-B that function for oxidation of monoamines. While MAO-A inhibitors are effective as antidepressant and anxiolytic drugs (e.g. chlorgyline, moclobemide, and lazabemide), inhibitors of MAO-B (e.g. Ldeprenyl, pargyline, and rasagiline) are used against neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. Considering the need for novel MAO inhibitors due to side effects of the current ones, natural products have become attractive targets for researchers. Up till now, many studies revealed strong MAO inhibitory activity of flavonoid, xanthone, alkaloid, and coumarin derivatives from herbal sources, which also become good models for the synthetic MAO inhibitors. For this purpose, the present review focuses on examples of in vitro and in vivo MAO-inhibiting natural compounds of plant origin from a wide variety of chemical classes isolated mainly between 2000 – 2015.

death [13, 14]. Consequently, inhibition of MAO is an important target and there is still a great need for development of novel MAO inhibitors due to their undesirable side effects of current inhibitors such as hepatotoxicity and well-known “cheese effect” depending on elevation of dietary tyramine levels occurred after MAO inhibition, dizziness, dry mouth, constipation, and blurred vision [15-18]. Natural products have always been a keystone in finding new lead molecules for drug candidates. Consistently, an extensive search has given rise to exploration of a growing number of natural products with prominent MAO inhibitory action i.e. flavonoids, alkaloids, xanthones, and coumarins [19]. In this review, compounds from several heterocyclic structures of natural origin reported in the literature primarily published between the years of 2000-2015 are aimed to cover in detail in order to emphasize the major role of natural products in discovery of new MAO inhibitors through in vitro and in vivo experiments as promising therapeutic opportunities. In the literature survey for the present review, databases and search engines including Web of Science, Pubmed, Scopus, and Google academic have been utilized.

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1. INTRODUCTION Monoamine oxidase (MAO, E.C. 1.4.3.4) is a flavin-containing enzyme family as an integral protein positioned in the surface membranes of mitochondria and also exists in neuronal and nonneuronal regions of the brain as well as peripheral organs [1]. Actually, it consists of two distinct subtypes, referred to MAO-A and MAO-B, both of which are expressed in the human brain, kidney, and liver tissues and can be distinguished through their specificity to substrates and selectivity to inhibitors as well as different amino acid sequence in their structures which are only 70% is identical [2, 3]. In this regard, L-deprenyl (syn. selegiline), pargyline, and rasagiline are more specific inhibitors toward MAO-B, where MAO-A is inhibited selectively by clorgyline, moclobemide, lazabemide, and esuprone. The subtypes are known to locate specific to organ and organisms. For instance; MAO-B is predominant in human brain, while MAO-A is the major subtype in rat brain. MAO-A plays a dominant role in the neurotransmitter serotonin (syn. 5hydroxytryptamine) metabolism, whose increase in the brain may donate to the pathogenesis of depression disorders [4]. In addition to serotonin, MAO-A has higher ability to catalyze the oxidative deamination of catecholamines and other biogenic amines such as norepinephrine, adrenaline, noradrenaline, etc. essential for neuronal functioning. On the other hand, MAO-B possesses more specific capability to catalyze the hydrophobic substrates containing benzylamine and 2-phenylethylamine [1, 5, 6]. On the other hand, dopamine as well as tyramine seems to be the more common amines catalyzed by both of A and B isoforms of this enzyme [7]. In fact, the first interest in MAO started around 1950s following discovery of MAO inhibitory property of iproniazide (an antituberculosis drug in original) which was also observed to improve the temper of the patients [8]. Selective MAO-A inhibitors proved to be effective antidepressants and anxiolytics, while MAOB inhibitors are implicated for treatment of Parkinson's (PD) and Alzheimer's diseases (AD) [9-11]. Particularly, MAO-B has been shown to be available at elevated levels in aging brains [12]. Actually, reaction with MAO leads to formation of aldehydes, hydrogen peroxide (H2O2), and ammonia as the end products, which causes cellular oxidation and cytotoxicity, finally prompting neuronal

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Keywords: Monoamine oxidase, enzyme inhibition, natural compounds, MAO, flavonoid, alkaloid, coumarin.

*Address correspondence to this author at the Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey; Tel: +90 312 202 3186; Fax: +90 312 223 5018; E-mail: [email protected] 1873-4286/16 $58.00+.00

2. NATURAL PRODUCTS WITH MAO INHIBITORY PROPERTIES 2.1. Flavonoids and Xanthones Many pharmacological activities desirable for human health have been so far reported for flavonoids as one of the largest chemical classes found in natural sources. Flavonoids contain an aromatic ring combined with a benzopyran ring having a phenyl substituent and exert desired pharmacological effects of central nervous system (CNS) due to their ability to pass the blood-brain barrier [20, 21]. For instance; flavonols, e.g. quercetin as well as hypericin, were suggested to be responsible for MAO inhibitory effect of Hypericum perforatum L. (Hypericaceae), the most prescribed herbal medicine for its marked antidepressant effect [22, 23]. A considerable number of flavonoid and other phenolics have been described with moderate to strong MAO-A or MAO-B inhibitory properties as listed in Table 1. In a study by Pan et al. [24], liquiritigenin and isoliquiritigenin (Fig. 1) isolated from Sinofranchetia chinensis (Franch.) Hemsl. (Lardizabalaceae) displayed a marked non-competitive type of inhibition with IC50 values of 32.0 and 13.9 mol/L against MAO-A and 104.6 and 47.2 © 2016 Bentham Science Publishers

Potential of Natural Products of Herbal Origin as Monoamine Oxidase Inhibitors

269

MAO inhibitory activity of selected flavonoids and phenolics expressed as IC50 values. Compounds

IC50 for MAO-A

IC50 for MAO-B

References

Liquiritigenin

32.0 mol/L

104.6 mol/L

[24]

Isoliquiritigenin

13.9 mol/L

47.2 mol/L

[24]

-6

a

NT

[25]

-6

1  10 M

NT

[25]

1.7 M

12.8 M

[32]

Quercitrin

NT

19.06 M

[26]

Isoquercitrin

NT

11.64 M

[26]

Rutin

NT

3.89 M

[26]

Luteolin

4.9 M

59.7 M

[32]

18.0 M

b

[29]

20 M

[28]

90 M

[32]

NT

[31]

10.89 M

[26]

NT

[25]

NT

[31]

NT

[25]

3.8 M

[33]

11.1 M

[34]

63.1 M

[34]

NT

< 1.0 M

[36]

-

88.6 M

[35]

955.0 M

IC50= 288.0 M

[39]

0.49 M

340.0 M

[40]

164.0 M

63.0 M

[40]

-

58.9 M

[35]

Xanthoangelol

43.4 M

43.9 M

[42]

Resveratrol

26.6 M

-

[43]

Veraphenol

38.0 M

-

[43]

Paeonol

54.6 M

42.5 M

[44]

Protocatechuic acid

2.41 Mol/L

300 Mol/L

[46]

Chrysin

2  10 M

Apigenin

-

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Table 1.

Current Pharmaceutical Design, 2016, Vol. 22, No. 3

0.01 M

19.6 M

O

2.8 M Quercetin

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NT

U

5  10-5 M

ut

17.5 M

Kaempferol

-7

Naringenin Gentiacaulein Gentiakochianin (-)-Epicatechin

rib is t

103.7 M

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(+)-Catechin

69.9 M

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Kushenol F

39.6 M

fo

Formononetin

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5-Hydroxyflavanone

al

7  10 M

a

Not tested b No inhibition

mol/L against MAO-B via mixed type of inhibition, respectively. Later on, kaempferol, apigenin, and chrysin obtained from Ginkgo biloba L. (Ginkgoceae) which were demonstrated with a pronounced in vitro inhibition on MAO-A and -B of rat brain origin were revealed to exert a potent inhibition against MAO-A (IC50= 7  10-7, 1  10-6, and 2  10-6 M, respectively). Kaempferol was concluded to be accountable mainly for MAO-A inhibitory effect of

the leaf extract of G. biloba [25], although neither the extract nor kaempferol showed inhibition ex vivo or on MAO from rat brain and liver. IC50 value of quercetin (Fig. 1) as well as the reference (phenelzine) was established as 5  10-5 M and 4  10-8 M, respectively in the mentioned study [25]. The authors also concluded that a phenyl (or hydroxylphenyl) ring as well as a double bond between the 2nd and 3rd positions in the flavonoid structure is accounted for

270 Current Pharmaceutical Design, 2016, Vol. 22, No. 3

Ilkay Erdogan Orhan OH

OH OH

HO

OH

HO

O

OH

O

OH

Isoliquiritigenin

HO

Quercetin

O OH

O

OCH3 OH

O OCH3

H3CO

O

Gentiacaulein

O

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Formononetin

O

is t

H3CO

CH3

OH

Paeonol

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Pe

Xanthoangelol

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O

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CH3

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U

HO

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OH

fo

Fig. (1). Structures of some flavonoids and phenolics with MAO inhibitory effect.

N ot

MAO inhibition. Besides, a single hydroxyl group on 2-phenyl group located at para position was mentioned to be necessary for occurrence of this effect. In another study [26], quercitrin, isoquercitrin, rutin, and quercetin isolated from the leaves of Melastoma candidum D. Don. (Melastomataceae) were found to inhibit MAOB in mixed-type of action potently with the IC50 values of 19.06, 11.64, 3.89, and 10.89 M, respectively, in comparison to that of the reference (L-deprenyl, IC50= 19.06 M) (Table 1). Considering structure-activity relationship, sugar moieties in the flavonoid structure were commented to play an important role in increase of MAO-B inhibitory activity. Similarly, quercetin was again disclosed to be the only MAO-inhibiting compound amongst five components [ursolic acid, quercetin-3-O--L-rhamnopyranosyl(16)--D-glucopyranoside, (-)-epicatechin, quercetin-3-O-D-galactopyranoside, and quercetin] isolated from the fruits of Crataegus pinnatifida Bunge (Rosaceae), also known as “Chinese hawthorn or Chinese hawberry” [27]. In a relevant study by Chimenti et al. [28], potent and selective MAO-A inhibitory activity of quercetin isolated from Hypericum hircinum L. (Hypericaceae) through bioassay-guided fractionation was proven with IC50 value of 0.01 M, while it was also able to inhibit MAO-B (IC50= 20 M) using kynuramine as the substrate. The molecular docking experiments confirmed that quercetin sits well into the active gorge of human MAO-A rather than MAO-B of human origin. Saaby et al. [29] demonstrated quercetin isolated from Calluna vulgaris (L.)

Hull. (Ericaceae) with a remarkable MAO-A-inhibiting effect (IC50= 18.0 M), while clorgylin (a specific MAO-A inhibitor) had the IC50 value of 0.2 M. Yoshino et al. [30] reported that quercetin administration in mice during seven days caused a reduction in MAO-A enzymatic activity, although it was weaker than the reference (clorgylin). Later on, quercetin and kaempferol isolated from Hypericum thasium Griseb. (Hypericaceae) were again found to be the strong MAO-A inhibitors expressed by the IC50 values of 19.6, and 17.5 M, respectively [31]. However, MAO-A-blocking potential of quercetin-3-O--l-arabinofuranoside was poor (IC50= 534.1 M). Among the flavonoid derivatives characterized as apigenin-7O--D-glucuronopyranoside, apigenin, luteolin, luteolin-7-O--Dglucopyranoside, (+)-dihydroquercetin (syn. taxifolin), (+)dihydrokaempferol (syn. aromadendrin), and quercetin from Cayratia japonica (Thunb.) Gagnep. (Vitaceae), apigenin, luteolin, and quercetin were established as the most effective MAO inhibitors with corresponding IC50 values of 6.5, 22.6, and 31.6 M (Table 1) [32]. In consistent with the aforementioned studies, more potent and selective inhibitory effect of quercetin towards MAO-A (IC50= 2.8 M) than MAO-B (IC50= 90.0 M) was proven. Similar to that of quercetin; apigenin and luteolin displayed a greater inhibition against MAO-A (IC50= 1.7 and 4.9 M, respectively). 5Hydroxyflavanone isolated from Gentiana lutea L. (Gentianaceae)

Potential of Natural Products of Herbal Origin as Monoamine Oxidase Inhibitors

271

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ble 1), whereas clorgyline (the reference drug) had IC50 value of 0.198 M [44]. Nevertheless, none of them were active against MAO-B. It was stated that glycosylation of the stilbenoids could decrease MAO-A inhibitory effect and free phenolic hydroxyl group appeared to be vital for inhibition. In another study [45], when four phenols (paeonol, honokiol, magnolol, and eugenol) were tested against MAO enzymes, only inhibition was observed by paeonol (2-hydroxy-4-methoxyacetophenone) (Fig. 1) (IC50= 42.5 M) against B subtype of the enzyme in competitive mode, while it inhibited MAO-A with IC50 value of 54.6 M (Table 1). Curcumin, a phenolic yellow pigment found in the rhizomes of Curcuma longa L. (Zingiberaceae), was shown to decrease MAO-A activity applied at 20 and 40 mg/kg, i.p. doses in in vivo experiments in dose-dependent manner, whereas it did not affect MAO-B enzymatic activity [46]. Protocatechuic acid (syn. dihydroxybenzoic acid) and 3,5-dihydroxy-1, 7-bis (4-hydroxyphenyl) heptane isolated from Gardenia jasminoides J. Ellis (Rubiaceae) displayed a marked inhibition against MAO-B (IC50= 300 and 196 mol/L, respectively), while a weaker MAO-A inhibitory effect was exhibited by these two compounds (IC50= 2.41 mMol/L and 400 mol/L, respectively) [47]. Three benzophenone compounds elucidated as 3,4,5-trihydroxy-6-methoxy-2-O--l-arabinosylbenzophenone (IC50= 310.3 M), 3,4,5,6-tetrahydroxy-2-O--l-arabinosylbenzophenone (IC50= 111.2 M), and 3,4-dihydroxy-5-methoxy-2O--l-arabinosyl-6-O- -d-xylosylbenzophenone (IC50= 726.0 M) isolated from Hypericum thasium Griseb. (Hypericaceae) were revealed with a low to moderate MAO-A inhibitory effect [31]. In a relevant work [48], the benzophenones, i.e. 2,3-dihydroxy-4methoxy-benzophenone-6-O-- glucopyranoside and 2,4,3,4tetrahydroxy-benzophenone-6-O--glucopyranoside (syn. maclurin6-O--glucopyranoside) from Gentiana verna L. subsp. pontica (Soltok.) Hayek (Gentianaceae) exhibited a significant inhibitory property against MAO-A (IC50=31.3±4 and 41±4.7 M, respectively).

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2.3. Coumarins A number of studies have defined potent MAO inhibitory effect caused by coumarin derivatives as highlighted in some recent reviews [49, 50]. For instance; two furocoumarin compounds; psoralen (Fig. 2) and isopsoralen, isolated from Psoralea corylifolia L. (Fabaceae), were reported to display a dose-dependent and reversible inhibition toward both MAO-A and -B enzymes (Table 2) [51]. Isopsoralen (IC50= 12.8 ± 0.5 M) was more effective against MAO-A than psoralen (IC50= 15.2 ± 0.5 M), while a weaker inhibition against MAO-B was caused by these two compounds. Consistently, Huong et al. [52] reported strong MAO inhibitory effect of psoralen (IC50= 21.3 M) and bergapten (IC50= 13.8 M) from Aquilaria agallocha Lamk. (syn. Aquilaria malaccense, Thymelaeaceae). Another coumarin compound elucidated as lacinartin (Fig. 2) from the stems of Zanthoxylum schinifolium Siebold & Zucc. (Rutaceae) inhibited both MAO-A (IC50= 5.7 M) and MAOB (IC50= 28.6 M) in non-competitive manner which was obviously more effective against MAO-A (Table 2) [53], while a dihydrocoumarin derivative [2-methoxy-3-(1,1´-dimethylallyl)-6a, 10adihydro-benzo(1, 2-c)chroman-6-one] isolated from Gentiana lutea showed a strong MAO-B (IC50= 2.9 M) and rather weak MAO-A (IC50= 100 M) inhibitory activity [33].

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was reported to be a MAO inhibitor since it displayed a potent inhibition against MAO-B (IC50= 3.8 M) and moderate level of inhibition against MAO-A (IC50= 39.6 M) [33]. The other two flavonoid derivatives, e.g. formononetin (IC50= 11.0 M) (Fig. 1) and kushenol F (IC50= 63.1 M), were the MAO-inhibiting constituents from the roots of Sophora flavescens Aiton (Fabaceae), both of which were more effective against MAO-B rather than MAO-A (Table 1) [34]. On the other hand, (+)-catechin and (-)-epicatechin separated from Uncaria rhynchophylla (Miq.) Jacks (Rubiaceae) possessed a moderate MAO-B-blocking potential (IC50= 88.6 and 58.9 M, respectively) as compared to that of the reference (L-deprenyl, IC50= 0.31 M) and identified as mixed-type of inhibitors by kinetic experiments [35]. In fact, MAO-B inhibitory effect of (+)-catechin in C6 astrocyte cells (IC50= < 1.0 M) was also previously reported by Mazzio et al. [36]. Three flavonoids, e.g. gancaonin A, 4-Omethylalpinumisoflavone, and alpinumisoflavone obtained from the fruits of Cudrania tricuspidata Bur. ex Lavallee (Moraceae), exerted a remarkable MAO inhibitory effect, where competitive MAO-B inhibitory effect of gancaonin A (IC50= 0.8 M) was significantly superior and selective in comparison with the two others [37]. The same plant species also afforded three more flavonoidtype of MAO (not specified) inhibitors at moderate level identified as kaempferol, artocarpesin, and cudraflavone D (IC50= 82.3, 30.8, and 71.8 M, respectively) [38]. Naringenin, a trihydroxyflavanone isolated from the leaf extract of Mentha aquatica L. (Lamiaceae), possessed low to moderate level of blocking potential against MAO (IC50= 342.0 M), MAO-A (IC50= 955.0 M), and MAO-B (IC50= 288.0 M), where corresponding IC50 values of chlorgyline (MAO-A inhibitor) and L-deprenyl (MAO-B inhibitor) were calculated as 0.0003 and 0.105 M [39]. The xanthone derivative; gentiacaulein (syn. 1,7-dihidroxy-3, 8dimethoxyxanthone) (Fig. 1) isolated from the aerial parts of Gentiana kochiana Perr. et Song. (Gentianaceae) was revealed to inhibit rat microsomal MAO-A (IC50= 0.49 M), whereas a low level of MAO-B inhibition was observed with gentiakochianin (1, 7, 8trihidroxy-3-methoxyxanthone) (IC50= 63.0 M) as well as gentiacaulein (IC50= 340.0 M) (Table 1) [40]. Bellidin and bellidifolin, two xanthone compounds isolated from Gentianella amarella (L.) Boerner subsp. acuta (Michaux) J. M. Gillett (Gentianaceae), were the potent MAO-A-inhibiting xanthone derivatives with 90.5 ± 0.5% and 98.9 ± 0.0% of inhibition tested at 10-5 M as compared to that of pargyline (the reference, 60.0 ± 1.8%) [41]. In the same study, MAO-B-inhibiting xanthones from the same species were revealed as swertianolin (93.6 ± 0.2%), corymberin 1-O-glucose (70.5 ± 1.0%), bellifolin (65.2 ± 5.0%), bellidin (59.0 ± 13.0%), and veratriloside (56.0 ± 1.6%). Very recently, 1,5,7-trihydroxy-3methoxyxanthone and 1,5-dihydroxy-3,7-dimethoxyxanthone isolated from the shoot cultures of Hoppea fastigiata (Griseb.) C.B. Clarke have been reported with promising MAO-A inhibitory effect in mixed and competitive manner, respectively, where 1,5dihydroxy-3,7-dimethoxyxanthone and 1,3,5-trihydroxy-8methoxyxanthone could inhibit MAO-B effectively [42]. Among two chalcone derivatives, i.e. xanthoangelol (Fig. 1) and 4-hydroxyderricin isolated from Angelica keiskei Koidzumi (Apiaceae), xanthoangelol exhibited an almost equal level of MAOA and -B inhibition (IC50= 43.4 and 43.9 M, respectively), which was closer to those of the reference (iproniazid, IC50=37 M, and 42.5 M) (Table 1) [43]. On the other hand, 4-hydroxyderricin (IC50= 3.43 M) displayed a significant inhibition towards MAO-B as compared to that of the reference (L-deprenyl, IC50= 0.046 M).

Current Pharmaceutical Design, 2016, Vol. 22, No. 3

2.2. Stilbenoids and Other Phenolics Among five stilbenoids elucidated as veraphenol, resveratrol, piceid, isorhapontin, and mulberroside E obtained from the roots and rhizomes of Veratrum taliense (Liliaceae), only veraphenol and resveratrol were identified to be the inhibitors of MAO-A (IC50= 26.6 and 38.0 M, respectively) acting in a competitive mode (Ta-

2.4. Alkaloids and Other Nitrogenous Compounds Earlier studies indicated that alkaloid derivatives could be promising inhibitors of MAO. For instance; in 1976, Giovine et al. [54] reported that salsolinol, tetrahydropapaveroline, N-methylisoquinoline, berberine, palmatine, ethaverine, and higenamine were the MAO inhibitors. Relevantly, the alkaloid fractions from Coptis japonica Makino (Ranunculaceae) rich in protoberberine alkaloids including berberine, palmatine, and coptisine strongly inhibited MAO [55]. When two benzophenanthridine type of alkaloids; san-

272 Current Pharmaceutical Design, 2016, Vol. 22, No. 3

Ilkay Erdogan Orhan

MAO inhibitory activity of selected natural compounds from various chemical classes expressed as IC50 values.

Table 2.

IC50 for MAO-A

IC50 for MAO-B

References

Psoralen

15.2 M

NTa

[50]

Isopsoralen

12.8 M

NT

[50]

Emodin

-b

35.4 M

[44]

Acetylshikonin

10.0 M

NT

[70]

Shikonin

13.3 M

NT

[70]

Shikonofuran E

59.1 M

NT

[70]

15,16-Dihydrotanshinone I

23 M

NT

[65]

Cryptotanshinone

80 M

NT

[65]

Tanshinone I

84 M

NT

[65]

Lacinartin

5.7 M

28.6 M

[52]

Harmine

4.54 M

-

[56]

91.3 M

[44]

7.0 M

[59]

223.0 mMol/L

[66]

780.0 mMol/L

[66]

-

[60]

306.6 M

[61]

162.8 M

[61]

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Compounds

Ursolic acid

-

Strictosidinic acid

150 g/mL

Lyaloside

50.04 M

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97.6 M

rD

13.92 M

17.08 g/mL

NT

[63]

NT

[64]

-

[67]

fo

Bacopaside I Not tested No inhibition

132.5 M

Pe

Pyrithione

io n

-

U

Geniposide

Desmodeleganine

b

se

20.9 M

Strictosamide

a

O

49.3 M Piperine

N ot

guinarine and chelidonine were assayed against MAO, only sanguinarine was elucidated with a marked inhibition (IC50= 24.5 M), while the reference (iproniazid) had IC50 value of 12.9 M [56]. Additionally, the molecular planarity of the phenathridine ring was concluded to be essential for MAO inhibition by this kind of alkaloids. Among harmine (syn. banisterin) (Fig. 2) and harmaline isolated from Banisteriopsis caapi (Spruce ex Griseb.) C.V. Morton (Malpighiaceae), harmine was identified as a potent MAO-A inhibitor of alkaloid type with IC50 value of 4.54 nM in concentrationdependent manner, where the reference (clorgyline) had IC50 value of 0.66 nM (Table 2) [57]. In accordance, other -carboline alkaloids including tryptoline (syn. 1,2,3,4-tetrahydro--carboline) and 1-methyltryptoline (syn. 1-methyl-1,2,3,4-tetrahydro--carboline) as well as aromatic -carbolines (e.g. norharman and harman) inhibited MAO-A well [58] and, in agreement, the high MAO-A inhibitory effect of the root and seed extracts of Peganum harmala L. (Zygophyllaceae) was attributed to their rich -carboline content such as harmine and harmol [59]. Kong et al. [45] tested seven alkaloid compounds (piperine, strychnine, brucine, stachydrine, tetrandrine, frangchinoline, and sinomenine) against both MAO-A and -B, in which only piperine (Fig. 2), a piperidine derivative as pungent substance found in

plants of the Piperaceae family including Piper nigrum L. (black pepper) and Piper longum L., exerted a marked inhibition against both enzymes (IC50= 49.3 M for A type and 91.3 M for B type) (Table 2). The kinetic studies indicated that inhibitory effect of piperine was mixed type for MAO-A and in competitive manner for -B isoform. In a similar study [60], piperine obtained from Piper longum L. was again described with a noteworthy inhibition against both MAO-A (IC50= 20.9 M) and MAO-B (IC50= 7.0 M). Nonetheless, this study indicated a higher MAO-B inhibitory effect of piperine in contrast to the results presented by Kong et al. [45]. Strictosidinic acid, a monoterpene indole alkaloid isolated from the leaf extract of Psychotria myriantha Mull. Arg. (Rubiaceae), was evaluated against MAO subtypes of rat brain mitochondrial origin and found to inhibit MAO-A with IC50 value of 150 g/mL, which was equal approximately 68.67% of inhibition (Table 2) [61]. However, the compound was not able to inhibit MAO-B at all. In another study [62], two monoterpene indole alkaloids, i.e. lyaloside (IC50= 50.04 M) and strictosamide (IC50= 132.5 M) found in Psychotria suterella Muell. Arg. and Psychotria laciniata Vell. Voucher. from Rubiaceae were more active MAO-A inhibitors in comparison to their MAO-B inhibitory actions (IC50= 306.6 and 162.8 M, respectively) (Table 2). The roots of Boerhaavia diffusa Linn. (Nyctaginaceae), locally known as known as “punarnava” in Mexico, yielded punarnavine an alkaloid which caused a

Potential of Natural Products of Herbal Origin as Monoamine Oxidase Inhibitors

Current Pharmaceutical Design, 2016, Vol. 22, No. 3

O

O

O

O

273

O

O

Psoralen

Lacinartin

O

N

N H

O

O

Shikonin

Harmine

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O

O

N H

io n

O

Desmodeleganine

ut

U

Piperine

is t

tion [67]. Bacopaside I, a saponin compound from Bacopa monniera, displayed a mixed mode of selective inhibition against human recombinant MAO-A (IC50= 17.08 ± 1.64 g/mL) (Table 2) [68].

rD

N ot

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significant decrease in MAO-A level in mouse brain [63]. Occurrence of high MAO-A inhibitory activity was also observed with desmodeleganine (IC50= 13.92 M) (Fig. 2), an indole alkaloid from the leaf extract of Desmodium elegans DC. (Fabaceae), a Chinese plant named as “shan mahuang” in comparison to iproniazid (IC50= 6.5 M) [64]. The molecular modeling studies pointed out that 3-hydroxy--ionone unit is imperative for this inhibition which helped to exhibit better hydrophobicity through increasing molecular volume along with surface area. The naturally occurring sulfur-containing nitrogenous compounds, i.e. pyrithione, 2-(methyldithio)pyridine N-oxide, 2[(methylthio)methyldithio]pyridine N-oxide, and di(2-pyridyl) disulfide N, N'-oxide isolated from the bulbs of Allium stipitatum Regel (Alliaceae) weakly inhibited MAO-A expressed by the IC50 values of 97.6, 139.0, 161.0, and 241.0 M, where clorgyline had IC50 value of 0.3 nM [65].

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Fig. (2). Structures of some natural MAO-inhibiting compounds.

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2.5. Terpenes and Iridoids A tanshinone-type of diterpenoid identified as 15, 16dihydrotanshinone I isolated from the root extract of Salvia miltiorrhiza Bunge (Lamiaceae), called locally “danshen” in China, was demonstrated with substantial inhibitory effect against human recombinant MAO-A with IC50 value of 23 M [66]. Low level of MAO-A inhibition was caused by cryptotanshinone (IC50= 80 M) and tanshinone I (IC50= 84 M) also obtained from the same plant species, where IC50 value of clorgyline (the selective MAO-A inhibitory drug) was 0.014 M (Table 2). The authors stated that aromatic ring along with dihydrofuran ring in the structure appeared to be important in inhibition of MAO-A. Selective MAO-B inhibitory action was demonstrated by the iridoid glycosides, geniposide (IC50= 223 mol/L) and 6'-O-transp-coumaroylgeniposide (IC50= 127 mol/L), obtained from Gardenia jasminoides, whereas ursolic acid from the same species showed poor MAO-B (IC50= 780 mol/L) and no MAO-A inhibi-

2.6. Quinone Derivatives During the search on finding novel MAO inhibitors, lemuninols A-C, new naphthoquinone derivatives isolated from Diospyros sp. (Ebenaceae), locally known as “lemuni hitam” in Malaysia, were revealed to have MAO inhibitory effect to some extent [69]. Among them, 45% inhibition against MAO was produced by lemuninol A at concentration of 5.0  10-6 g/mL, whereas the other two compounds of the series were very weak in this assay. On the other hand, 1-methyl-2-undecyl-4(1H)-quinolone from the fruits of of Evodia rutaecarpa (Juss.) Benth. (Rutaceae) was found to have a selective inhibition against MAO-B (IC50= 15.3 M) using kynuramine as the substrate in competitive mode (Ki value of 9.91 M), while it did not show any inhibition against MAO-A [70]. Kong et al. [45] tested six anthraquinone derivatives (emodin, rhein, chrysorphanol, aloe-emodin, physcion, and 1,8- dihydroxyanthraquinone) against two MAO isoforms and only emodin (3methyl-1,6,8-trihydroxyanthroquinone) had mixed type of inhibition selectively toward MAO-B (IC50= 35.4 M) (Table 2). In another study by Woo et al. [71], three naphthoquinones; acetylshikonin, shikonin (Fig. 2), and shikonofuran E obtained from the roots of Lithospermum erythrorhizon Siebold & Zucc. (Boraginaceae) were reported to possess a strong MAO-A inhibiting effect with corresponding IC50 values of 10.0, 13.3, and 59.1 M (Table 2). CONCLUSION In the current review, a number of herbal-originated compounds possessing mainly flavonoid, xanthone, alkaloid, coumarin, and quinone structures have been covered referring to their MAO in-

274 Current Pharmaceutical Design, 2016, Vol. 22, No. 3

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Flavonoids and xanthones

Stilbenoids and other phenolics

Terpenes and iridoids MAO INHIBITION BY NATURAL COMPOUNDS

Quinone derivatives

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LIST OF ABBREVIATIONS AD = Alzheimer's disease CNS = Central nervous system IC = Inhibitory concentration MAO = Monoamine oxidase PD = Parkinson's disease

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ACKNOWLEDGEMENTS Declared none. REFERENCES

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CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.

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hibitory potentials from low to moderate and potent levels (Fig. 3). Among these chemical classes, flavonoid and alkaloid derivatives appear to have a higher capacity to inhibit MAO. At this point, a special emphasize should be given to quercetin as it seems to be the most promising natural compound with potent and selective MAOA inhibitory effect which could be the subject of further studies to develop a new antidepressant drug molecule. Additionally, the alkaloids with -carboline and indole skeletons as well as piperine deserve a particular attention due to their strong inhibitory ability toward MAO. In conclusion, the data gathered in this review underlines once more the importance and necessary role of natural compounds in drug discovery process.

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Fig. (3). MAO-inhibiting natural compound classes.

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276 Current Pharmaceutical Design, 2016, Vol. 22, No. 3

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Accepted: November 11, 2015

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Received: August 1, 2015

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Ilkay Erdogan Orhan