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. Author manuscript; available in PMC: 2013 Jun 8.
Published in final edited form as: Phytother Res. 2012 Aug 8;27(6):818–828. doi: 10.1002/ptr.4795

High throughput Screening to Identify Natural Human Monoamine Oxidase B Inhibitors

E Mazzio 1, S Deiab 1, K Park 2, KFA Soliman 1,*
PMCID: PMC3521852  NIHMSID: NIHMS401750  PMID: 22887993

Abstract

Age-related increase in monoamine oxidase B (MAO-B) may contribute to CNS neurodegenerative diseases. Moreover, MAO-B inhibitors are used in the treatment of idiopathic Parkinson disease as preliminary monotherapy or adjunct therapy with L-dopa. To date, meager natural sources of MAO-B inhibitors have been identified, and the relative strength, potency and rank of many plants relative to standard drugs such as Selegiline (L-deprenyl, Eldepryl) are not known. In this work, we developed and utilized a high throughput enzyme microarray format to screen and evaluate 905 natural product extracts (0.025–.7 mg/ml) to inhibit human MAO-B derived from BTI-TN-5B1-4 cells infected with recombinant baculovirus. The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis-matrix assisted laser desorption ionization-time-of-flight-tandem mass spectroscopy, and enzyme activity was confirmed by [1] substrate conversion (3-mM benzylamine) to H202 and [2] benzaldehyde. Of the 905 natural extracts tested, the lowest IC50s [<0.07 mg/ml] were obtained with extracts of Amur Corktree (Phellodendron amurense), Bakuchi Seed(Cyamopsis psoralioides), Licorice Root (Glycyrrhiza glabra/uralensis), Babchi (Psoralea corylifolia seed). The data also show, albeit to a lesser extent, inhibitory properties of herbs originating from the mint family (Lamiaceae) and Turmeric, Comfrey, Bringraj, Skullcap, Kava-kava, Wild Indigo, Gentian and Green Tea. In conclusion, the data reflect relative potency information by rank of commonly used herbs and plants that contain human MAO-B inhibitory properties in their natural form.

Keywords: monoamine oxidase, Parkinson’s, herbs, natural medicine, MPTP, dopamine

INTRODUCTION

Monoamine oxidase (MAO, EC 1.4.3.4) is a mitochondrial membrane bound flavin-containing enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters such as dopamine (DA). Due to the function role of MAO in regulation of DAergic neurotransmission, enzyme inhibitors have become of relevant pharmacological interest for treating diseases associated with DAergic malfunction such as Parkinson’s disease (PD) and depression (Drozak and Kozlowski, 2006; Horn et al., 2010). In the case of PD, type B MAO (MAO-B) inhibitors are used in early to advanced disease states, alone or adjunct to DA agonists such as levodopa, pramipexole, ropinirole, rotigotine or entacapone (Rascol et al., 2011). MAO-B inhibitors are primarily used to modulate symptomatic defect in motor control, by augmenting efficacy of Sinemet creating rise in synaptic DA concentrations (Talati et al., 2009) and in some cases providing a time delay for PD patient requirement to commence traditional levodopa treatment (Lohle and Reichmann, 2011).

Much of the literature suggests that MAO-B inhibitors not only modulate DAergic function, but also impart neurological protection (Polanski et al., 2011) and thereby slow the progressive nature of PD (Lohle and Reichmann, 2011; Fedorova et al., 2011; Pagonabarraga and Kulisevsky, 2010). However, the protective effects of MAO-B inhibitors are still in question, with uncertainty as to distinction between symptomatic or etiological relief associated with the inhibition of MAO or other properties of this class of drugs (Kassubek et al., 2010; van Laar et al., 2010). For example, some studies show that the N-propargyl moiety in/or metabolites formed from rasagiline such as 1-(R)-aminoindan antagonize apoptosis, thereby introducing powerful neuroprotective properties. (Weinreb et al., 2010) Independent of MAO inhibition, rasagiline also prevents mitochondrial permeability, cytochrome c release, casapase activation, DNA damage and affords rise in neurotrophic factors (Naoi and Maruyama, 2009) and neurorescue against post- N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated damage in mice. (Mandel et al., 2007)

A rise in capacity or expression of MAO-B is believed to contribute to age-related neurological injury due to aggravated accumulation of 3,4-dihydroxyphenylacetaldehyde, which is readily metabolized to 3,4-dihydroxyphenylacetic acid, free radicals and orthoquinones which provoke oxidative neurological damage. (Anderson et al., 2011; Jinsmaa et al., 2011) Transgenic mice over expressing MAO-B show substantial oxidative stress and inflammation within the SN, with elevated levels of H202 which can oxidize DA to dopaminochrome (a mitochondrial toxin) (Mallajosyula et al., 2008; Siddiqui et al., 2010)

While inhibitors of type B monoamine oxidase (MAO-B) such as rasagiline and L-deprenyl are candidate drugs for treatment of PD, it has also been suggested that natural products as in the case of Banisteriopsis caapi contain MAO-B inhibitory properties. (Wang et al., 2010). With public interest in this enzyme for treatment of PD and neurological diseases associated with aging of the brain, and very little information on standardized screenings for natural MAO-B inhibitors, we screen and rank 905 products sold worldwide. Extracts included diverse range of natural products from sectioned fresh fruits, fresh vegetables, seeds, rinds, herbs, roots cut and dried to cultural spices often used as Chinese and Indian traditional medicines.

METHODS AND MATERIALS

Hanks Balanced Salt Solution, (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) (HEPES), iodoacetamide, DL-Dithiothreitol (DTT), ethanol, 96 well plates, vanillic acid, 4-aminoantipyrine, general reagents and supplies, MAOb and supplies were all purchased from Sigma Scientific (Sigma, St Louis MO). Natural products were provided by Frontier Natural Products Co-op (Norway, IA), Monterey Bay Spice Company (Watsonville, CA), Mountain Rose Herbs (Eugene, OR), Mayway Traditional Chinese Herbs (Oakland, California), Kalyx Natural Marketplace (Camden, NY), Futureceuticals (Momence, IL), organic fruit vegetable markets and Florida Food Products Inc. (Eustis, FL).

Herbal extraction

Plant and herbal extracts were macerated, diced, chopped and homogenized in 100% ethanol at 50 mg/ml. Samples were placed on a rocker shaker for 24 h and stored in air tight containers at −20°C in the dark. All serial dilutions were made using a diluent consisting of HBSS with 10-mM HEPES adjusted to a pH 7.4.

MALDI MS MS protein identification

Human MAO-B was derived from insect cells (BTI-TN-5B1-4) infected with recombinant baculovirus containing cDNA for human MAO-B (Sigma, St Louis MO). The protein was validated by proteomic analysis using matrix assisted laser desorption ionisation (MALDI) Mass Spec (MS/MS) and analyzed by Mascot ID. Briefly, 10 μg of pure enzyme was solubilized, denatured and subjected to 1 D SDS page gel electrophoresis using a 5–20% Tris-HCL gradient gel with a running buffer 25 mM Tris, 192 mM glycine, 0.1% SDS at 200 V for 35 min. High intensity bands for MAO-B at 60 Kd were excised, followed by in gel digestion of peptides with trypsin following reduction/alkylation with DTT and iodoacetamide respectively. Samples were analyzed using MALDI MS/MS (Applied Biosystems) and protein sequence identified by Mascot analysis.

Monoamine oxidase activity

A continuous MAO-B assay was used to conduct high throughput screenings with slight modifications (Holt and Palcic, 2006). Briefly, MAO-B was prepared in HBSS containing 10-mM HEPES, pH 7.4 at a concentration of 3.5 U/ml HBSS. The enzyme and treatments were distributed in 96-well microplates and incubated at RT for 10 min. The substrate [benzylamine] (final working concentration 3 mM) and chromogen from a 5× stock [5-mM vanillic acid, 2.5-mM 4-aminoantipyrine and 4 U/ml of horseradish peroxidase type II] were added to each well. Addition of the substrate (1:5 v/v) and the chromogenic solution (1:5 v/v) initiated the reaction, which required 18–24 h at RT for completion. Product formation was quantified every 4 h. At time zero, plates were quantified for O.D. at 490 nm to obtain a pre plate reading accounting for background. For data analysis, the post plates readings at time 4, 8,12,16, 20 and 24 h were obtained by subtracting the time zero pre-plate reading to monitor only the continuous product accumulation (increase in O.D at 490 nm).

High throughput design

We designed a model for rapid screening based on the concept used in PCR microarrays for gene amplification. An enzyme microarray format was adopted to where a 96-well plate contained known concentration of enzyme, and 905 treatments of equal concentration dissolved in buffered HBSS were incubated with the enzyme, prior to start of the reaction with the substrate and chromogen. After addition of the substrate, a curve for time-dependent product formation was monitored continuously over 24 h. A first tier investigation was established at a final working concentration of 0.7 mg/ml for each herbal extract. Any compounds that inhibited MAO-B with in the first tier screen below 50% of control were then placed in a second (final concentration = .4 mg/ml), third tier (final concentration =.2 mg/ml) and fourth tier (final concentration =.07 mg/ml). Extracts were ranked for potency, and the most potent were further evaluated for IC50 s along with deprenyl as a positive control. The enzyme microarray format is very rapid, reproducible and validated by triplicates and corroborated by a four tier evaluation process.

Benzaldehyde production

Quantification of benzaldehyde was continuously monitored using a Shimadzu high-performance liquid chromatography (HPLC) system equipped with an SPD-20A UV detector (set at 254 nm), a workstation containing EZSTART version 7.4 software and an SS420X instrument interface docked to a Waters Autosampler Model 717 Plus (Shimadzu Scientific Instruments, Inc. US; Waters Corp., Milford, MA). Benzaldehyde standard curves were established, and samples taken from the enzyme reaction chamber were mixed with 2x distilled water and then 50:50 with methanol prior to injection. The flow rate was isocratic at 1.2 ml/min. The mobile phase consisted of 10-mM sodium phosphate (pH 2.7) mixed at 45:55 with methanol. The column was a TSK-gel ODS-100 V 5 μm 4.6 mm (id) × 15.0 cm (L); (Tosoh Corporation), the run time was 6 mins and injection volume 25 μl.

Determination of H+ concentration

Although we used 10-mM HEPES buffered HBSS (pH 7.4) as a diluent, due to the high number of compounds and potential for pH to contribute to inhibitory effects in the enzyme reaction, in particular for acidic fruits, a high throughput evaluation for pH was conducted in 96-well plates using standard phenol red indicator dye. Briefly, extract matrix blanks for extracts displaying inhibitory properties were evaluated for influence on pH by establishing a pre-plate reading at 550 nm using a Spectra 190-MAX UV spectrophotometric detector (Molecular devices, Sunnydale, CA, USA) and post plate reading after addition of phenol red stock solution (0.2 mg/ml water) in HBSS (15% v/v) to each well. The change in pH was immediately assessed relative to control blanks at 550 nm relative to control blanks. Any extracts that altered the pH of the reaction vessel were buffered to pH 7.2 and re-evaluated at neutral pH for MAO-B inhibition.

Determination of H202 Non enzymatic stoichiometric radical scavenging

Due to the high number of compounds and potential for antioxidant effects to yield a false positive for MAO-B inhibitor identification (an enzyme reaction that monitors continuous production of H2O2), all extracts at concentrations demonstrating MAO-B inhibitor activity were evaluated for ability to scavenge peroxide 30 μM. Briefly, H2O2 was incubated in the presence of experimental compounds at RT for 20 min. A pre-plate reading was obtained where the data was subtracted from the final value to eliminate background interference. The chromogenic reagent (5x stock [5-mM vanillic acid, 2.5-mM 4-aminoantipyrine and 4 U/ml of horseradish per-oxidase type II]) was added to each sample and incubated for 10 min at 37°C. Samples were analyzed at 490 nm using a Spectra 190-MAX UV spectrophotometric detector (Molecular devices, Sunnydale, CA, USA). Extracts showing ability to scavenge peroxide were validated by HPLC via quantification of benzaldehyde.

Data analysis

Statistical analysis was performed using Graph Pad Prism (version 3.0; Graph Pad Software Inc. San Diego, CA, USA) with significance of difference between the groups assessed using a one-way ANOVA, followed by Tukey post hoc means comparison test, a two-way ANOVA or Student’s t test. IC50s were determined by regression analysis using Origin Software (OriginLab, Northampton, MA).

RESULTS

Method validation was established by monitoring the continuous time-dependent product formation in the presence of a substrate (benzylamine 2 mM) ± MAO-B ± Selegiline (L-deprenyl) (100 μM) (Fig. 1a [H202] and Fig. 1b [benzaldehyde]). The data show a slow but steady rate of reaction, resulting in time-dependent product formation with high signal/noise ratio. Protein sequencing using MALDI MS/MS and analysis by Mascot ID showed a positive hit for human MAO-B with a 95% confidence interval for peptide/sequence mass (Fig. 2). MAO-B positive controls were established using a known inhibitor [L-deprenyl] which showed significant potency and a complete loss of product formation [H202] and [benzylamine] at 1 μM (Fig. 3a and 3b). The data reflect a greater sensitivity observed by HPLC quantification of benzaldehyde than color-imetric assessment of H202 despite similar trends in enzyme inhibition.

Figure 1.

Figure 1

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A. Human MAO-B activity - Time-dependent H202 product formation from 3-mM benzylamine in the presence or absence of human MAO-B, and in the presence of 3-mM benzylamine + 100 μM of deprenyl. The data represent μM H202 produced from 0–18 h (incubation at RT) and are presented as the Mean ± S.E.M, n=4. Significance of difference for product formation between the Time 0 control versus 2–18 h was determined using a one-way ANOVA followed by a Tukey post hoc test * p< .05. B. Human MAO-B activity - Time-dependent benzaldehyde product formation from 3-mM benzylamine in the presence or absence of human MAO-B, and in the presence of 3-mM benzylamine + 100 μM of deprenyl. The data represent μM benzaldehyde produced from 1–12 h (incubation at RT) and are presented as the Mean ± S.E.M, n=4. Significance of difference for product formation between the time 1 h versus 6 and 12 h was determined using a one-way ANOVA followed by a Tukey post hoc test. * p< .05. This figure is available in colour online at wileyonlinelibrary.com/journal/ptr.

Figure 2.

Figure 2

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Mascot results for protein identification by peptide mass fingerprinting of Human MAO-B tryptic digest analyzed by MALDI-TOF/TOF-MS. This figure is available in colour online at wileyonlinelibrary.com/journal/ptr.

Figure 3.

Figure 3

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A. Deprenyl inhibitory effects on Human MAO-B. The data represent product formation (μM benzylamine) produced at 24 h (incubation at RT) in the presence or absence of deprenyl (82 – 1000 nM) and are presented as the Mean ± S.E.M, n=4. Significance of difference for product formation between the controls versus deprenyl was determined using a one-way ANOVA followed by a Tukey post hoc test. * p<.05. B. Deprenyl inhibitory effects on Human MAO-B. The data represent product formation (μM H202) produced at 24 h (incubation at RT) in the presence or absence of deprenyl (82 – 375 nM) and are presented as the Mean ± S.E.M, n=4. Significance of difference between the controls versus activity in the presence of deprenyl was determined using a one-way ANOVA followed by a Tukey post hoc test. * p<.05. This figure is available in colour online at wileyonlinelibrary.com/journal/ptr.

A high throughput enzyme microarray model was developed and used in this work as described in Fig. 4. We designed a model for rapid screening based on a similar concept often applied in microarray analysis for quantitative real-time RT-PCR. However, instead of gene amplification, an enzyme microarray format was adopted to where a 96-well plate contained known concentration of enzyme and 905 treatments of equal concentration dissolved in buffered HBSS were incubated with the enzyme, prior to start of the reaction. After addition of the substrate, a curve for time-dependent product formation was monitored continuously over 24 h. A first tier investigation was established at a final working concentration of 0.7 mg/ml for each herbal extract. Any extract that inhibited MAO-B with in the first tier screen below 50% of control was then subject to a second (final concentration = .4 mg/ml), third tier (final concentration =.2 mg/ml) and fourth tier (final concentration =.07 mg/ml). A total of 905 extracts were evaluated at a final working concentration of .7 mg/ml. Of these, 133 demonstrated an IC50 < 0.7 mg/ml. Of the 133 retested at .4 mg/ml, 66 extracts showed an IC50 <0.4 mg/ml. Of the 66 retested at .2 mg/ml, 26 extracts showed an IC50 <0.2 mg/ml. Of the 26 retested at .2 mg/ml, five extracts showed IC50 <0.07 mg/ml. All extracts showing inhibitory properties were evaluated for potential interfering variable of pH shifts or radical scavenging abilities (which would render false positive based on MAO-B activity based on formation of H202). False positives were eliminated by adjusted pH and confirmed by benzaldehyde product accumulation by HPLC. All inhibitors are listed in Table 1 where extracts demonstrating the greatest potency are listed as Level 1 (strongest) IC50 <.07 mg/ml, followed by Level 2 (strong) IC50 <.2 mg/ml, Level 3 (moderately strong) IC50 >.2<.4 mg/ml, Level 4 (moderate) (IC50>.4 < .7 mg/ml) and Level 5 (weak) IC50=.7 mg/kg. The most potent natural MAO-B inhibitors were identified, confirmed and an IC50 established (Fig. 5). The findings in this study yield evidence to suggest there are a number of natural products commonly used worldwide which have capacity to inhibit human MAO-B enzyme. However, in the therapeutic range, the most likely candidates were Amur Cork tree, Licorice, Psoralea Fruit and Bakuchi.

Figure 4.

Figure 4

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A high throughput enzyme experimental microarray design. 905 extracts were evaluated for capacity to inhibit Human MAO-B. A first tier screening was conducted at a final working concentration of 0.7 mg/ml for each herbal extract. Enzyme activity was continuously monitored over a 24-h period. Extracts demonstrating an IC50 <0.7 mg/ml were screened through a tier 2 screening at .4 mg/ml. Extracts demonstrating an IC50 at <0.4 mg/ml were screened through a tier 3 screening at .2 mg/ml. Extracts demonstrating an IC50 at <0.2 mg/ml were screened through a tier 4 screening at .07 mg/ml.. All extracts showing inhibitory properties were evaluated for potential interfering variable of pH shifts or radical scavenging abilities (which would render false positive based on MAO-B activity based on formation of H202). This figure is available in colour online at wileyonlinelibrary.com/journal/ptr.

Table 1.

Human MAO-B inhibitors by potency. Extracts demonstrating the greatest potency are listed as Level 1 (strongest) IC50 <.07 mg/ml, followed by Level 2 (strong) IC50 <.2 mg/ml, Level 3 (moderately strong) IC50 >.2<.4 mg/ml, Level 4 (moderate) (IC50>.4 < .7 mg/ml) and Level 5 (weak) IC50=.7 mg/kg

Natural plant sources of human MAO-B inhibitors

LEVEL ID Common name Scientific name Inhibitory conc.
LEVEL 1 A9 Amur Cork Tree Phellodendron amurense IC50 <.07 mg/ml
B54 Bakuchi Seed a Cyamopsis psoralioides IC50 <.07 mg/ml
L2 Licorice Root Glycyrrhiza glabra IC50 <.07 mg/ml
G22 Gan Cao a Glycyrrhiza uralensis root IC50 <.07 mg/ml
P58 Psoralea Fruit Babchi a Psoralea corylifolia IC50 <.07 mg/ml
LEVEL 2 P15 Beefsteakplant a Perilla frutescens leaf IC50 <.2 mg/ml
W4 Black Pepper Piper nigrum IC50 <.2 mg/ml
B15 Bringraj ‘False Daisy’ Eclipta erecta IC50 <.2 mg/ml
C34 Chinese arborvitae a Truja, Platycladus orientalis twig/leaf IC50 <.2 mg/ml
C2 Comfrey Symphytum officinale leaf IC50 <.2 mg/ml
C84 Curry powder Coriander, turmeric, cumin, fenugreek, red pepper IC50 <.2 mg/ml
F4 Figwort Scrophularia nodosa IC50 <.2 mg/ml
S54 Gloryvine Stem Sargentodoxa cuneata IC50 <.2 mg/ml
XT3 Green Tea Camellia sinensis IC50 <.2 mg/ml
H20 Herb de province Oregano, thyme, savory, lavender, basil, sage, rosemary IC50 <.2 mg/ml
K8 Kava Kava Piper methysticum IC50 <.2 mg/ml
L45 Ladys’ Mantle Alchemilla vulgaris IC50 <.2 mg/ml
A37 Lesser Galangal Alpinia officinarum Root IC50 <.2 mg/ml
L35 Red Henna Lawsonia inermis IC50 <.2 mg/ml
C53 Sappanwood Caesalpinia sappan wood IC50 <.2 mg/ml
D10 Thick-stemmed Wooda Dryopteris crassirhizoma IC50 <.2 mg/ml
T3 Turmeric a Curcuma Longa IC50 <.2 mg/ml
W13 Watercress Nasturtium officinale IC50 <.2 mg/ml
W3 Wild Indigo Root Baptisia tinctoria IC50 <.2 mg/ml
W10 Wild lettuce Lactuca virosa IC50 <.2 mg/ml
G6 Yellow Gentian Root Gentiana lutea IC50 <.2 mg/ml
LEVEL 3 A4 Alfalfa Medicago sativa IC50 >.2 <.4 mg/ml
A48 Alpinia Alpinia katsumadai seed IC50 >.2 <.4 mg/ml
B48 Bay Leaf Laurus nobilis IC50 >.2 <.4 mg/ml
B13 Bayberry Root bark a Morella cerifera IC50 >.2 <.4 mg/ml
C103 Cedar Berries Juniperus monosperma IC50 >.2 <.4 mg/ml
C101 Celandine Chelidonium majus IC50 >.2 <.4 mg/ml
S56 Common hedgenettle Stachys officinales IC50 >.2 <.4 mg/ml
E3 Eucalyptus Leaf Eucalyptus globulus IC50 >.2 <.4 mg/ml
E6 Eyebright Euphrasia officinalis IC50 >.2 <.4 mg/ml
D18 Fringed Pink Dianthus superbus IC50 >.2 <.4 mg/ml
G31 Garam Marsala Garam Marsala IC50 >.2 <.4 mg/ml
G28 Gourmet pepper mill Gourmet pepper mill IC50 >.2 <.4 mg/ml
G29 Gunpowder green tea Camellia sinensis IC50 >.2 <.4 mg/ml
H22 Hyssop Hyssopus officinalis IC50 >.2 <.4 mg/ml
P89 Indian long pepper Piper longum IC50 >.2 <.4 mg/ml
I2 Isatis Leaf Isatis indigotica; Isatis tinctoria IC50 >.2 <.4 mg/ml
I8 Italian spice herbal tea Italian spice herbal tea IC50 >.2 <.4 mg/ml
K9 Kola Nut Cola acuminata IC50 >.2 <.4 mg/ml
L43 Lemon Curry Lemon curry IC50 >.2 <.4 mg/ml
L49 Lemon Verbana Aloysia triphylla IC50 >.2 <.4 mg/ml
M20 Lilly Tree Magnolia denudata flower IC50 >.2 <.4 mg/ml
L46 Linden Leaf Tilia europaea IC50 >.2 <.4 mg/ml
M38 Maiden Hair Fern Adiantum capillus IC50 >.2 <.4 mg/ml
M40 Motherwort Leonurus cardiaca IC50 >.2 <.4 mg/ml
P4 Parsley Petroselinum crispum IC50 >.2 <.4 mg/ml
R4 Red Clover Trifolium pratense IC50 >.2 <.4 mg/ml
R9 Red Sandlewood Pterocarpus santalinus IC50 >.2 <.4 mg/ml
L33 Rough bugleweed Lycopus lucidus IC50 >.2 <.4 mg/ml
S61 Sage Salvia officinalis IC50 >.2 <.4 mg/ml
S23 Sassafras Sassafras Albidum IC50 >.2 <.4 mg/ml
E21 Scouringrush horsetail Equisetum Heimale IC50 >.2 <.4 mg/ml
S32 Skull cap a Scutellaria barbata IC50 >.2 <.4 mg/ml
S16 Skull cap a Scutellaria lateriflora IC50 >.2 <.4 mg/ml
S64 Spearmint a Mentha spicata IC50 >.2 <.4 mg/ml
S20 Stevia/Candyleaf Stevia rebaudiana IC50 >.2 <.4 mg/ml
S15 Szechuan pepper Zanthoxylum bungeanum IC50 >.2 <.4 mg/ml
W11 White Sage Salvia apiana IC50 >.2 <.4 mg/ml
Y8 Yohimbe Bark Corynanthe yohimbe IC50 >.2 <.4 mg/ml
Y7 Young Hyson Green Tea Camellia sinensis IC50 >.2 <.4 mg/ml
V1 Zi Hua Di Ding Viola yedoensis herb IC50 >.2 <.4 mg/ml
LEVEL 4 ID Common Name Scientific Name Inhibitory Conc.
A67 Ancho chili pepers Capsicum annum IC50 >.4 < .7 mg/ml
B19 Blackberry leaf Rubus fruticosus IC50 >.4 < .7 mg/ml
B12 Blackberry Root Rubus fruticosus or Rubus Villosus IC50 >.4 < .7 mg/ml
F17 Bladderwrack Fucus vesiculosus IC50 >.4 < .7 mg/ml
B26 Blessed Thistle Cnicus benedictus IC50 >.4 < .7 mg/ml
C1 California Poppy Eschscholzia californica IC50 >.4 < .7 mg/ml
C87 Catnip a Nepeta cataria IC50 >.4 < .7 mg/ml
H16 Chameleon Houttuynia cordata herb IC50 >.4 < .7 mg/ml
c80 Cilantro Leaf Coriandrum sativum IC50 >.4 < .7 mg/ml
C39 Cinnamon Twig Cinnamomum cassia IC50 >.4 < .7 mg/ml
C9 Cleavers Galium aparine IC50 >.4 < .7 mg/ml
A49 Clematis trifoliata Akebia trifoliata fruit IC50 >.4 < .7 mg/ml
D1 Damiana Leaf Turnera diffusa IC50 >.4 < .7 mg/ml
E24 Earlgrey black tea Earlgrey black tea IC50 >.4 < .7 mg/ml
E23 Elder berries Sambucus nigra IC50 >.4 < .7 mg/ml
E2 Epidedium Epimedium grandiflorum IC50 >.4 < .7 mg/ml
E15 Epidedium Epimedium koreanum IC50 >.4 < .7 mg/ml
F2 Feverfew Tanacetum parthenium IC50 >.4 < .7 mg/ml
C17 Garden Chervil Anthriscus cerefoilium IC50 >.4 < .7 mg/ml
G30 German chamomile Matricaria recutita IC50 >.4 < .7 mg/ml
G37 Goats Rue Galega officinalis IC50 >.4 < .7 mg/ml
G8 Great Valley gumweed Grindelia camporum IC50 >.4 < .7 mg/ml
L3 Gromwell root Lithospermum erythrorhizon root IC50 >.4 < .7 mg/ml
G4 Gymnema Gymnema sylvestre IC50 >.4 < .7 mg/ml
H3 Hops, whole Humulus lupulus IC50 >.4 < .7 mg/ml
H8 Horsetail Equisetum arvense IC50 >.4 < .7 mg/ml
P14 Japenese Indigo Polygonum tinctorium levis IC50 >.4 < .7 mg/ml
K2 Kombu Laminaria setchellii IC50 >.4 < .7 mg/ml
L6 Lily of the valley Convallaria majalis IC50 >.4 < .7 mg/ml
L23 Lysimachia Lysimachia christinae IC50 >.4 < .7 mg/ml
M32 Marjoram a Origanum majorana IC50 >.4 < .7 mg/ml
M31 Melilot Herb Melilotus vulgaris IC50 >.4 < .7 mg/ml
M34 Mint Mentha haplocalyx IC50 >.4 < .7 mg/ml
M39 Mistle Toe Phoradendron flavescens IC50 >.4 < .7 mg/ml
M8 Mugwort Artemisia vulgaris IC50 >.4 < .7 mg/ml
M36 Mullein leaf Verbascum thapsus IC50 >.4 < .7 mg/ml
P12 Papaya Leaf Carica papaya IC50 >.4 < .7 mg/ml
P5 Peach leaf Prunus persica IC50 >.4 < .7 mg/ml
P81 Pennyroyal Mentha pulegium IC50 >.4 < .7 mg/ml
P56 Peony Paeonia suffructicose root - bark IC50 >.4 < .7 mg/ml
P79 Peppermint a Mentha piperita IC50 >.4 < .7 mg/ml
P88 Periwinkle Vinca minor IC50 >.4 < .7 mg/ml
P3 Plantain Herb Plantago asiatica IC50 >.4 < .7 mg/ml
P85 Plantain Leaf Plantago major IC50 >.4 < .7 mg/ml
R21 Red rose And Petals Rosa damascena IC50 >.4 < .7 mg/ml
R2 Redroot Ceanothus americanus IC50 >.4 < .7 mg/ml
C77 Senna Leaf Cassia angustifolia leaf IC50 >.4 < .7 mg/ml
S19 Shepards Purse a Capsella bursa-pastoris IC50 >.4 < .7 mg/ml
L7 Spice Bush Lindera aggregata root IC50 >.4 < .7 mg/ml
S33 Spikemoss Selaginella doederleinii IC50 >.4 < .7 mg/ml
S60 Spiralina powder Arthrospira platensis IC50 >.4 < .7 mg/ml
S72 Spirulina Arthrospira platensis IC50 >.4 < .7 mg/ml
C40 Spreading sneezeweed Centepida mimima IC50 >.4 < .7 mg/ml
S3 Strawberry Leaf Fragaria vesca IC50 >.4 < .7 mg/ml
S28 Sweet Grass Braid Hierochlöe Odorata IC50 >.4 < .7 mg/ml
T1 Tansy Tanacetum vulgare IC50 >.4 < .7 mg/ml
T5 Tarragon Artemisia dracunculus IC50 >.4 < .7 mg/ml
C95 Tea Celyon (black tea) IC50 >.4 < .7 mg/ml
T2 Thyme Leaf a Thymus vulgaris IC50 >.4 < .7 mg/ml
S68 Toothache Plant Spilanthes acmella IC50 >.4 < .7 mg/ml
S22 Touch me not Speranskia tuberculata IC50 >.4 < .7 mg/ml
T30 Turkey Rhubarb Rheum palmatum IC50 >.4 < .7 mg/ml
V2 Vervain Verbena officinalis herb IC50 >.4 < .7 mg/ml
W16 White Willow Bark Salix alba IC50 >.4 < .7 mg/ml
P73 Wintergreen Pyrola calliantha IC50 >.4 < .7 mg/ml
W8 Wormwood Artemisia absinthum IC50 >.4 < .7 mg/ml
A44 Wormwood Artemisia capillaris IC50 >.4 < .7 mg/ml
LEVEL 5 A41 Agrimony Agrimonia pilosa IC50≈.7 mg/kg
S74 Alexandrian Senna Senna alexandrina IC50≈.7 mg/kg
A6 Asafoetida Ferula Assa-Foetida IC50≈.7 mg/kg
D9 BAI CAI GAN Dried Chinese Cabbage IC50≈.7 mg/kg
B27 Black Berry Powder Rubus armeniacus IC50≈.7 mg/kg
I7 Black Henna Indigofera tinctoria IC50≈.7 mg/kg
C91 Cayenne powder Capsicum annuum IC50≈.7 mg/kg
V6 Chaste Tree Berry Vitex agnus-castus IC50≈.7 mg/kg
C12 Chickweed Stellaria media IC50≈.7 mg/kg
P29 Chinese Cinquefoil Potentilla chinensis IC50≈.7 mg/kg
T24 Dandelion Root Taraxacum mongolicum IC50≈.7 mg/kg
D5 Dill weed Anethum graveolens IC50≈.7 mg/kg
A26 Dogbane Apocynum venetum herb IC50≈.7 mg/kg
F20 Fennel seed a Foeniculum vulgare IC50≈.7 mg/kg
F22 Fringe Bark Tree Chionanthus virginicus IC50≈.7 mg/kg
F23 Fumitory Fumaria officinalis IC50≈.7 mg/kg
G27 Garcinia cambogia Garcinia cambogia IC50≈.7 mg/kg
G23 Gardenia Gardenia jasminoides fruit IC50≈.7 mg/kg
S31 Japanese Catnip Schizonepeta tenuifolia IC50≈.7 mg/kg
P22 Knotweed Grass Polygonum aviculare IC50≈.7 mg/kg
M37 Malva Flower Malva sylvestris IC50≈.7 mg/kg
N11 Nettle stinging Urtica dioica IC50≈.7 mg/kg
O18 Oatstraw Avena sativa IC50≈.7 mg/kg
O14 Orange peel Citrus sinensis IC50≈.7 mg/kg
O12 Oregano leaf a Origanum vulgare IC50≈.7 mg/kg
O2 Osha Root Ligusticum porteri IC50≈.7 mg/kg
P27 Patrinia Patrinia villosa herb IC50≈.7 mg/kg
P28 Purslane Portulaca oleracea IC50≈.7 mg/kg
R8 Raspberry Leaf Rubus idaeus IC50≈.7 mg/kg
H29 Strawflower Helichrysum foetidum IC50≈.7 mg/kg
E25 Tea English breakfast black tea IC50≈.7 mg/kg
I9 Tea Irish breakfast green tea IC50≈.7 mg/kg
S41 The Holy Herb Siegesbeckia orientalis IC50≈.7 mg/kg
P18 Tongue fern Pyrrosia Lingua IC50≈.7 mg/kg
G26 Wintergreen Gaultheria procumbens IC50≈.7 mg/kg
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a

Botanical Replicates confirmed from various distributors.

Figure 5.

Figure 5

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Most potent herbal extract inhibitors of human MAO-B activity. The data represent product formation (H202) as % control produced at 24 h (incubation at RT) in the presence or absence of extracts (.025–.8 mg/ml) and are presented as the Mean, n=4. IC50 concentrations were established from a sigmoidal fit dose–response equation and significance of difference between the controls versus treatment was determined using a one-way ANOVA followed by a Tukey post hoc test * p<.05. This figure is available in colour online at wileyonlinelibrary.com/journal/ptr.

DISCUSSION

In this study, we screened 905 natural product extracts to elucidate potential sources of human MAO-B inhibitors. The data elucidate a number of new potential sources and specify the relatively few that inhibited MAO-B within therapeutic range. The herbal extracts showing greatest potency included Amur Corktree (Phellodendron amurense), Licorice Root (Glycyrrhiza glabra and Glycyrrhiza uralensis), Psoralea Fruit (Psoralea corylifolia (PC)) and Bakuchi Seed (Cyamopsis psoralioides). While it is outside the scope of this paper to review all MAO-B inhibitors identified, we will focus the discussion on the most potent elucidated.

New findings presented from this work show potent MAO-B inhibitory capacity inherent within Bakuchi seed, an otherwise understudied aryurvedic historical medicine most known for treatment of vitiligo, where it is associated with regeneration of melanocytes (Dhanik et al., 2011). It is of interest to note that this plant also contains constituents such as psoralens or hydroxybakuchiol which promote skin pigmentation (Khushboo et al., 2010) augment melanin dispersal (Sultan and Ali, 2011) and augment central DAergic function due to direct inhibition of the DA transporter, making it a likely candidate for treatment of PD (Zhao et al., 2007).

In this study, one of the most interesting findings (also corroborated by others) was the MAO-B inhibitory effects of psoralens or furocoumarins (derived from PC seeds), which impart anti-depressant effects via reduction of stress evoked plasma cortisol (Chen et al., 2005; Chen et al., 2007; Kong et al., 2001) and protect against MPTP-induced DAergic loss within substantia nigra in mice. (Zhao et al., 2009) The anti-depressant properties of PC also correspond to the elevation of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, as well as rise in striatal DA, effects which are concomittent to reduction of stress-evoked serum corticotropin-releasing factor and adrenal corticotropin-releasing hormone, suggesting a number of neurotransmitter systems are affected. (Yi et al., 2008; Xu et al., 2008).

While future research will have to be initiated on PC and Bakuchi seed, a plethora of existing work demonstrates a range of therapeutic values that exist outside the scope of PD, including a potential to treat cancer and osteoarthritis, (Ming et al., 2011), reduce bone loss (Lim et al., 2009) treat bacterial/viral infections or inflammatory related disease (Szliszka et al., 2011; Yang et al., 2011; Li et al., 2011; Khushboo et al., 2010). In addition, constituents within PC have been well characterized and known to include several classes of compounds; e.g. psoralenoside (benzofuran glycosides), psoralen, isopsoralen, psoralidin (coumarins), bakuchiol (meroterpenes) (Qiu et al., 2011; Song et al., 2011) corylifolean, corylifolin, bakuchicin, isobavachin, bavachinin, bavachalcone, isobavachalcone, corylin, corylidin, bavachromene, astragalin, p-hydroxybenzoic acid stigmasterol, triaconate and β-sitosterol-D-glucoside (Khushboo, Jadhav, 2010).

Glycyrrhiza glabra/uralensis

In a strikingly similar pattern to that of PC, existing research also shows capacity of Glycyrrhiza glabra to reduce stress response in mice through elevating brain concentrations of norepinephrine and DA comparable to that of tricyclic anti-depressant drugs; imipramine and fluoxetine (Dhingra and Sharma, 2006). The data from the current work also corroborate the effects of glycyrrhiza uralensis and glabra roots to have MAO inhibitor capacity with reported IC50 at .03 mg/ml (Tanaka et al., 1987; Hatano et al., 1991a) where the same Hatano et al. also define a number of licorice constituents such as licopyranocoumarin licocoumarone and glycyrrhisoflavone being responsible for MAO inhibition. (Hatano et al., 1991b).

Licorice is a highly studied natural medicine, with therapeutic values ranging from anti-inflammatory properties in microglial BV2 cells, neuroprotective properties against 6-hydroxydopamine cytotoxicity/MPTP nigrostriatal DAergic degeneration in mice (Kim et al., in press) and reduction of glutamate-mediated excitotoxicity associated with hippocampal neuronal cell death.(Yang et al., 2012) Many of these therapeutic properties appear to enhance the case for licorice in therapeutic potential application for PD.

Unlike, other herbs referenced in this study, there is meager research on therapeutic effects or characterization of Amur Corktree Phellodendron amurense in relation to any aspect of DAergic neurotransmission. However, recent interest in this plant surrounds its anti-inflammatory and anti-cancer properties, in addition to preventing osteoarticular cartilage and chondrocyte destruction. (Xian et al., 2011; Kim et al., 2011; Ghosh et al., 2010) Future research will be required to further investigate therapeutic aspects of Amur Corktree in processes inherent to degenerative disease specific to PD.

As a note, in the past, we had investigated a number of compounds for MAO inhibitory activity in foods on a very small scale and at that time had eluded to the fact that green tea catechins and curcumin were likely candidate MAO-B inhibitors.(Mazzio et al., 1998) Since then, a number of studies have examined this and shown green tea components such as epigallocatechin gallate and curcumin supplementation exert reduction of brain MAO-B enzyme activity in rats (Lin et al., 2010), effects which are synergist with rasagiline in PD mice models (Ashizawa and Sano, 1990) and administration which has reversed MPTP induced loss of DA. (Rajeswari and Sabesan, 2008) The findings from this current study broaden our view of potential MAO-B candidates yielding a number of herbs potentially more or equally as promising to green tea or turmeric.

The identification of new natural or synthetic MAO-B inhibitors which provide therapeutic advantage in treatment of PD must be viewed in light of differential selectivity from MAO-A, due to risk of hypertensive crisis in the presence of tyramine containing foods. Although, it is estimated that the adverse effects are less than previously believed (Gillman, 2011), in particular for rasagiline selectivity when used at the recommended dose (Chen and Wilkinson, 2012; Isaacson, 2010) (Goren et al., 2010), future potential drug development should include a tyramine challenge control for in vivo animal studies.

In conclusion, the findings from this paper open up new areas for future research specifying specific natural plants with capacity to inhibit MAO-B, that could lead to medicines with greater capacity to treat diseases associated with maladaptive DAergic function with in the CNS.

Acknowledgments

This research was supported by a grant from NIH NCRR RCMI program (G12RR 03020) and the National Institute of Minority Health and Health Disparities, NIH (8G12MD007582-28 and 1P20 MD006738-01).

Footnotes

Conflict of Interest

The authors have declared that there is no conflict of interest.

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