Herbal Natural Products as a Source of Monoamine Oxidase Inhibitors: A review.
ABSTRACT Drugs of natural origin still play a major role in the treatment of many diseases and as lead structures for the development of new synthetic drug substances. This review article deals the pharmacological effects on the Central Nervous System (CNS) of some plant extracts and their isolated chemical components due to their monoamine oxidase (MAO) activity. Herbs and herbal preparations containing MAO-A inhibitors have been widely used as an effective alternative in the treatment of neuropsychiatric diseases such as depression. Inhibitors of MAO-B not only enhance dopaminergic neurotransmission but also prevent activation of toxin and free radical formation, alleviating the process of neuron denaturalization, on account of which they are used in Parkinson disease (PD). Several methods have been developed for monitoring MAO activity and its inhibitor screening of bioactive natural products.
- Pharmacology Biochemistry and Behavior 06/2003; 75(3):497–499. · 2.61 Impact Factor
Article: Enzymology of monoamine oxidase.Cell Biochemistry and Function 05/1986; 4(2):79-87. · 1.85 Impact Factor
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ABSTRACT: Monoamine oxidase (MAO), a mitochondrial outer membrane enzyme, catalyzes the degradation of neurotransmitters in the central nervous system and is the target for anti-depression drug design. Two subtypes of MAO, MAOA and MAOB, are similar in primary sequences but have unique substrate and inhibitor specificities. The structures of human MAOB complexed with various inhibitors were reported early. To understand the mechanisms of specific substrate and inhibitor recognitions of MAOA and MAOB, we have determined the crystal structure of rat MAOA complexed with the specific inhibitor, clorgyline, at 3.2A resolution. The comparison of the structures between MAOA and MAOB clearly explains the specificity of clorgyline for MAOA inhibition. The fitting of serotonin into the binding pockets of MAOs demonstrates that MAOB Tyr326 would block access of the 5-hydroxy group of serotonin into the enzyme. These results will lead to further understanding of the MAOA function and to new anti-depression drug design. This study also presents that MAOA has a transmembrane helix at the C-terminal region. This is the first crystal structure of membrane protein with an isolated transmembrane helix.Journal of Molecular Biology 05/2004; 338(1):103-14. · 3.91 Impact Factor
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Current Topics in Medicinal Chemistry, 2012, 12, 2131-2144
Herbal Natural Products As a Source of Monoamine Oxidase Inhibitors: A
Dolores Viña1, Silvia Serra2, Manuel Lamela1 and Giovanna Delogu2*
1Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782-Santiago de
Compostela, Spain; 2Dipartimento di Scienze della Vita e dell’Ambiente, Facoltà di Farmacia, Università degli Studi di
Cagliari, 09124-Cagliari, Italy
Abstract: Drugs of natural origin still play a major role in the treatment of many diseases and as lead structures for the
development of new synthetic drug substances. This review article deals the pharmacological effects on the Central Nerv-
ous System (CNS) of some plant extracts and their isolated chemical components due to their monoamine oxidase (MAO)
activity. Herbs and herbal preparations containing MAO-A inhibitors have been widely used as an effective alternative in
the treatment of neuropsychiatric diseases such as depression. Inhibitors of MAO-B not only enhance dopaminergic neu-
rotransmission but also prevent activation of toxin and free radical formation, alleviating the process of neuron denaturali-
zation, on account of which they are used in Parkinson disease (PD). Several methods have been developed for monitor-
ing MAO activity and its inhibitor screening of bioactive natural products.
Keywords: Natural products, central nervous system, MAO-A inhibitors, MAO-B inhibitors, neuroprotection.
dicinal purposes. The presence of medicinal plants was al-
ways a very important chapter in all of the world pharmaco-
poeias until the 1940-50 years. Later, synthetic drugs dis-
placed medicinal plants in medical therapeutics. However
nowdays, 80% of the world population has no access to
modern health care system and therefore to synthetic drugs
. For them, medicinal plants still represent the main
source of disease treatments. In addition, 25% of drug pre-
scriptions in industrialized countries contain ingredients di-
rectly or indirectly related to plants . Several topic exam-
ples concern to the Central Nervous System (CNS) and in-
clude caffeine, ephedrine, cannabinoids, opioids and reser-
pine. However, the majority of active principles from CNS
active plants are not yet known. The rational treatment of
CNS disorders by plant extract-derived drugs is in its infancy
due to the complex chemistry and organization of the CNS
and also to the complex chemistry and pharmacology of a
plant extract . This review article deals with the pharma-
cological effects on the CNS of some plant extracts related to
their monoamine oxidase (MAO) activity.
From beginning of History, man has used plants for me-
enzyme located at the outer mitochondrial membranes in the
brain, liver, intestinal mucosa and other organs and catalyzes
the oxidative deamination of biogenic amines (neurotrans-
mitters, vasoactive and xenobiotic amines), including dopa-
mine, serotonin, norephinephrine, tyramine, tryptamine and
MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neu-
rotoxin [4-6]. MAO appears as two isozymes, MAO-A and
MAO is a flavin-adenine-dinucleotide (FAD)-containing
*Address correspondence to this author at the Dipartimento di Scienze della
Vita e dell’Ambiente, Facoltà di Farmacia, Università degli Studi di Ca-
gliari, 09124-Cagliari, Italy; Tel: +390706758571; Fax: +390706758553;
MAO-B, distinguished by their differences in substrate and
inhibitor selectivities. MAO-A preferentially catalyzes the
oxidation of serotonin and norepinephrine and is inhibited by
clorgyline, whereas MAO-B selectively catalyzes the oxida-
tion of phenylethylamine and benzylamine and is inhibited
by (R)-deprenyl. Tyramine, dopamine and tryptamine appear
to be substrates for both enzymes [7, 8]. MAO plays a sig-
nificant physiological role in the CNS and peripheral organs.
Abnormal activity of MAO-B is implicated in neurological
disorders such as Parkinson’s (PD) and Alzheimer’s diseases
(AD), whereas MAO-A plays an important role in psychiat-
ric conditions such as depression . The oxidation of bio-
genic amines by MAO results in the production of hydrogen
peroxide and aldehydes which may represent a risk factor for
cell oxidative injury . Therefore, identification of MAO
inhibitors is of a great interest in drug discovery.
HERBAL MEDICINES SHOWING MAO-A ACTIVITY
AS ANTIDEPRESSANT TREATMENT
do not adequately respond to commonly prescribed medica-
tions, such as selective serotonin reuptake inhibitors (SSRIs)
. Thus, it becomes necessary to find a more effective
antidepressant treatment. Historically, the MAO inhibitors
did so irreversibly, they inhibited both MAO-A and MAO-B,
and their main side effect was the tyramine intolerance, then
dietary restrictions were required in order to avoid hyperten-
sive crisis. Recent advances are involved with the develop-
ment of selective and reversible MAO-A inhibitors, such as
moclobemide, and MAO inhibitor compounds with a high
ratio of brain-to-periphery concentrations . In the CNS,
MAO-A activity can regulate the extracellular concentration
of serotonin by metabolizing serotonin incorporated into the
presynapses through presynaptic transporters. One important
reason to develop MAO-A inhibitors is that they closely
Half of the people with major depressive disorder (MDD)
1873-5294/12 $58.00+.00 © 2012 Bentham Science Publishers
2132 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20
Viña et al.
match one aspect of the pathophysiology of MDD, since
greater MAO-A binding occurs in patients with MDD. Dur-
ing major depressive episodes MAO-A binding is elevated
by 30% in affect-modulating brain regions .
In Oriental countries, herbs and herbal preparations have
been widely used as an effective alternative in the treatment
of neuropsychiatric diseases such as depression. In the
search of new herb extracts showing MAO-A inhibitory
properties, a dichloromethane extract of the root of Salvia
miltiorrhiza Bunge (Lamiaceae), a well known Chinese
herbal drug, displayed a marked inhibitory effect on rat liver
MAO with a preference for the MAO-A isoenzyme .
Veratrum taliense Loes (Liliaceae) yielded, from methanol
extract of roots and rhizomes, five stilbenoids which are
MAO-A inhibitors . Anemarrhena asphodeloides Bunge
(Liliaceae), also commonly found in traditional Chinese
herbal medicines, has been shown to have antidepressant
effects in mouse models of behavioral despair test. Sar-
sasapogenin, the major active component of A. asphodeloi-
des, at doses of 12.5, 25 and 50 mg/Kg reduced in a dose
dependent manner the duration of immobility in the forced
swimming test. This activity is comparable to the reference
drug fluoxetine .
nut in the Indo-Pak subcontinent which has been used for
masticatory purpose by people living in different parts of the
world. It has been previously reported that the nut has psy-
choactive  and antidepressant effects . The di-
chloromethane fraction obtained from a crude extract of this
nut appears to be more potent to inhibit monoamine oxidase
type A isolated from the rat brain (IC50 = 665 ± 65.1 μg/ml)
than the initial extract and other fractions. Studies with
pharmacological models of depression, i.e., forced swim and
tail-suspension tests, indicated that it causes significant re-
duction in the immobility time similar to that of moclobe-
mide (a selective inhibitor of MAO-A) without causing a
significant change in motor performance .
Areca catechu L. (Arecaceae) is a very popular chewing
L. (Zingiberaceae) has been used since immemorial times in
Ayurvedic medicine. Diverse biological actions are known,
including its antidepressant activity, so dose dependently
inhibits MAO-A activity, whereas MAO-B inhibitory activ-
ity is observed only at higher doses. The enhanced brain lev-
els of serotonin observed in mice, following the curcumin
administration (10-80 mg/Kg, i.p.), may be related to the
inhibition of MAO-A enzyme, whilst MAO-B inhibition
results in the increase in central dopamine levels. Both these
activities, by enhancing the availability of serotonin and do-
pamine in the brain, are responsible for its antidepressant
activity. Coadministration with piperine may provide a use-
ful natural adjuvant in the antidepressant therapy because the
bioavailability of curcumin is increased . Piperine is best
known as the pungent principle of the black pepper (Piper
nigrum L. Piperaceae) and is also a MAO inhibitor .
Curcumin, a major active component of Curcuma longa
sus Willd (Asparagaceae) to improve the physical and men-
tal faculties rising defense mechanisms of the body and en-
hancing longevity. It has been reported to possess antide-
pressant activity, possibly mediated through the mono-
aminergic system .
Ayurvedic medicine also recognized Asparagus racemo-
the Arabian Peninsula and is used in local folk medicine
practices to treat diabetes mellitus, certain inflammatory
conditions and helminthiasis but this shrub also shows anti-
depressant and sedative actions which could be explicable in
terms of different components. Whilst a weakly basic chloro-
form fraction causes an increase in MAO-A inhibitory activ-
ity, butanol extracts brought about a decrease . Using the
forced swimming test , the immobility time in R. stricta
treated rates exhibits a biphasic effect on the immobility
time. The lower doses (0.1, 0.2 and 0.4 g/Kg) elicit a highly
significant and inversely dose-dependent decrease in immo-
bility time, whereas the higher doses (0.8, 1.6 and 6.4 g/Kg)
show a dose-dependent decrease in immobility time .
Rhazya stricta Decne (Apocynaceae) grows commonly in
showing MAO-A inhibitor properties for the treatment of
neuropsychiatric diseases. Therefore, Melissa officinalis L.
(Lamiaceae) has traditionally been used in all around the
world to prepare a tea for its sedative and spasmolytic ef-
fects; a great variety of phytopharmaceutical preparations
containing this plant are available in the market by its effects
on nervous system. Both methanolic and aqueous extracts
from the leaves inhibit MAO-A activity relieving depression
symptoms and might protect neurons from oxidative stress
although methanolic extract is more effective than the aque-
But not only Oriental Society has used herbs extract
miaceae) are used as dietary constituent to improve attention,
mood and memory, extracts from Origanum vulgare L. (La-
miaceae) may comprise a workable strategy to maintain a
healthy mood status and enhance mental well-being in hu-
mans. Oregano extract, comprising a specified range of ac-
tive constituents, acts as a moderate, natural, reuptake inhibi-
tor of serotonin (5-HT), noradrenalina (NA) and dopamine
(DA), in addition to inhibit monoamine catabolism in vitro.
It inhibits dependently and reversibility the enzymatic activ-
ity of MAO-A. The reversibility of the inhibition is very
important in order to prevent side effects such as orthostatic
hypotension and hypertensive crisis, as associated to the ear-
lier MAO inhibitors .
As well as M. officinalis and Salvia officinalis L. (La-
has been used in some European countries for its sedative
effect. Ethyl acetate fraction obtained from a methanolic
extract shows MAO-A inhibition due to its content of quer-
cetin . Quercetin, a flavonoid, has been also isolated
from Hypericum hircinum L. (Hypericaceae) and some oth-
ers Hypericum species such as H. polyanthemum, H. caprifo-
liatum and H. piriai. The lipophilic extract of these plants
contain benzopyran derivatives displaying MAO-A inhibi-
tory activity . Also H. perforatum L. is used as a treat-
ment for major depressive episodes and it remains one of the
top-selling herbal products in the United States. However a
recent study, after 6 weeks of treatment in depressed patients
(600 mg of St. John´s worth twice daily), shows a negligible
effect on MAO-A binding in vivo and therefore, should not
be classified as an antidepressant MAO-A inhibitor .
Flavonoids are also present in the 70% ethanol extract of
Mentha aquatic L. (Lamiaceae), medicinal plant traditionally
used in southern Africa for depression-like conditions for
MAO-inhibitory activity, which has high activity. Narin-
Also the tea of heather of Calluna vulgaris L. (Ericaceae)
Herbal Natural Products As a Source of Monoamine Oxidase Inhibitors Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20 2133
genin, which was isolated from the extract by bioassay
guided fractionation, has been shown to pass the blood-brain
barrier which means that it can exercise an effect on the CNS
Flavonoids contained in Sinofranchetia chinensis Diels
(Lardizabalaceae) inhibit MAO-A and MAO-B enzymes
being more active against MAO-A isoform which is inhib-
ited in a non-competitive way, it implies that they combining
to different sites of the enzyme to produce a “head-end”
complex and are thus independing of the pre-binding of 5-
Nowadays, internet access represents a new information
mechanism to the use of illicit substances. There exit already
numerous websites providing information on Peganum har-
mala L. (Zygophyllaceae) and Banisteriopsis caapi Morton
(Malpighiaceae) potentially leading to an increase in their
unsafe use. Indeed, urban people imitate the shamans and
prepare Ayahuasca imitations with P. harmala and other
plants. Ayahuasca refers to the vine made with several spe-
cies of Banisteriopsis usually in combination with other
plants, such as Psycotria viridis Ruiz & Pav. (Rubiaceae) or
Diplopterys cabrerana Ott. (Malpighiaceae) which are being
the principle ingredient of a psychoactive beverage used by
different indigenous groups spread along Brazil, Colombia,
Peru, Venezuela, Bolivia and Ecuador . The potent inhi-
bition of MAO-A results from the interaction with ?-
carboline alkaloid contained in these plants could be the ba-
sis for its purported antidepressant actions but also should
contribute to the psycopharmacological and toxicological
HERBAL MEDICINES SHOWING MAO ACTIVITY
FOR PARKINSON TREATMENT
often presents with symptoms of rest tremor, bradykinesia,
rigidity and stooped posture. The exact cause of this disease
still remains a mystery that hampers the development of
proper therapeutic interventions. Despite many approaches
and efforts, to data no researchers have been successful in
developing a cure or at least a modality to check the disease
and most of the therapies only provide functional relief. Evi-
dence suggests that immense oxidative stress, free radical
formation, genetic susceptibility and programmed cell death
all have a role in the development of Parkinson´s disease.
The neuropathology of this disease is based on depigmenta-
tion and cell loss in the dopaminergic nigrostriatal tract of
the brain, with the corresponding decrease in the striatal do-
pamine concentrations . Standard therapy consists in
giving L-dihydroxyphenylalanine (L-DOPA), which crosses
the blood-brain barrier and is converted into dopamine in the
brain. Although, in the short term, L-DOPA is effective in
controlling the symptoms of PD, it often results in unpredict-
ability and involuntary movements so other therapeutic
agents are being sought. Approaches to compounds having a
similar net effect may involve compounds acting as dopa-
mine agonists, those that stimulate the release of dopamine
from cells where it is produced or stored in the brain and
those elevating dopamine levels by inhibition of MAOs. In-
hibitors of MAO-B not only lead to enhanced dopaminergic
neurotransmission but also prevent activation of toxin and
free radical formation and the alleviated the process of neu-
ron denaturalization .
PD is one of the major neurodegenerative disorders and
with symptoms similar to PD, although interest died quickly,
more recently, reports have described the beneficial use of an
extract of Banisteriopsis caapi Morton (Malpighiaceae),
containing ?-carboline derivatives, on patients with PD .
B. caapi and harmine show a concentration-dependent inhi-
bition of MAO-A but little effect on MAO-B activity using
liver homogenate. However, the extract increases signifi-
cantly the in vitro release of DA from rat striatal slices. The
potent antioxidant action of this plant, has a significant
added value for the protection of neuronal cells damage by
oxidative free radicals [38, 39].
In 1920s and early 1930s harmine was used in patients
presso and regular coffee. As coffee is the main exogenous
source of these alkaloids in addition to cigarette smoking,
accumulation of these compounds in regular coffee drinkers
might locally affect MAO-A/B metabolism of both exoge-
nous amines and neuroamines and most importantly this may
have an eventual neuroprotective action against PD .
?-carboline derivatives are also present in instant, es-
species and its leaves are among the most extensively stud-
ied herbs in use today. Although Chinese herbal medicine
has used both the ginkgo leaf and seed for thousand of years,
modern research has focused on the standarized G. biloba
extract (EGb) which is made from the dried green leaves. M.
Ahmad et al. have reported a significant restoration of stri-
atal DA and its metabolites following the treatment with
EGb. EGb (50, 100 and 150 mg/Kg for 3 weeks) was evalu-
ated for its anti-parkinsonian effects in a 6-hydroxydopamine
(6-OHDA) rat model of the disease. The increase in drug-
induced rotations and deficits in locomotor activity and mus-
cular coordination due to 6-OHDA injections were signifi-
cantly and dose-dependently restored by EGb. G. biloba ap-
pears to act via antioxidant, free radical scavenging, DA-
enhancing mechanism that rescues the compromised cells
within the dopaminergic lesions and MAO-B inhibiting 
although the effect of EGb on cerebral MAO activity is more
probably a down-regulation than a simple inhibition .
Salvia miltiorrhiza Bunge (Lamiaceae), previously here
described by its MAO-A inhibitory properties, might provide
a useful therapeutic strategy for the treatment of PD. It has
been suggested that one of its components, salvianic acid A,
has a neuroprotective effect ascribed to its antioxidative
properties and anti apoptotic activity via regulating the
expression of Bcl-2 and Bax. In addition, S. miltiorrhiza has
showed inhibitory effects on MAO-B in rat brain homogen-
Ginkgo biloba L. (Ginkgoaceae) is the oldest living tree
different pharmacological purposes, very little research has
investigated the relationships between these traditional me-
dicinal plants and MAO-B activity. Polygonum multiflorum
Thunb. (Polygonaceae), has been used for anti-aging purpose
in Chine since ancient times. The extract of the plant was
found to be inhibitory against MAO-B probably due to its
10-dione) contain . Lin et al. studied the MAO-B activ-
ity of a selection of 27 aqueous methanolic extracts derived
from 13 families useful in Chinese medicine and they found
extracts of Arisaema amurense Maxim (Araceae), Lilium
brownii F.E. Brown (Liliaceae) var. Colchesteri Wils, Ly-
Although Chinese herbal medicine is widely used with
2134 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20
Viña et al.
cium chinense Mill (Solanaceae) and Uncaria rhynchophylla
(Miq.) Jacks (Rubiaceae) as most active and selective .
generally used to treat convulsive disorders. However, it has
also been found to show neuroprotective effects because
inhibiting tumor necrosis factor-? (TNF-?) and nitric oxide
production in BV-2 mouse microglial cells in vitro. Al-
though different extracts showed MAO-B inhibitory effects,
MAO activity is fundamentally due to (+)-catechin and (-)-
epicatechin which are also abundant in green tea (GT) .
GT acts like true antioxidants such as vitamin C being
protective of neurons at low concentrations, while at higher
concentrations becomes pro-oxidant. However like GT ex-
tract inhibits striatal MAO-B at high concentrations, MAO
inactivation is not involved in neuroprotection exerted by
GT. GT extract (0.5 and 1 mg/Kg) and its main constituent
(-)-epigalochatechin-3-galate (EGCG; 2 and 10 mg/Kg) have
demonstrated their neuroprotective properties in MPTP mice
model of PD. EGCG is easily absorbed from the digestive
tract and is widely achieves distributed into various organs,
including brain, which has a similar concentration to that of
the liver. Pretreatment of mice with EGCG completely pre-
vented catalase induction by MPTP neurotoxin and reduced
superoxide dismutase (SOD) levels in brain at low concen-
tration but does not affect the activities of SOD and catalase
in liver indicating selectivity of EGCG on the antioxidant
capacity in the brain .
In the course of screening for bioactive compounds from
botanical sources, it was found that the ethyl acetate extract
of the dried bark of Gentiana lutea L. (Gentianaceae)
potently inhibits rat brain MAO being a dihydrocoumarin the
most potent inhibitor against MAO-B among its components.
In addition G. lutea has been reported to have scavenging
activity toward hydroxyl radical and antioxidative properties
Hook of U. rhynchophylla (Miq.) Jacks (Rubiaceae) is
found in Geijera parviflora Lindl. (Rutaceae) , Dictam-
nus albus L. (Rutaceae)  and Monascus anka Nakazawa
et Sato (Monascaceae) .
Coumarins with MAO-B inhibitory properties were also
a tropical or subtropical plant which was introduced to sea-
side area of Cheju Island, Korea. Currently it is cultivated for
use in manufacturing health foods such as tea, drinks and
noodles. It was found that the ethyl acetate extract of fruits
shows inhibitory activity from MAO-B .
Opuntia ficus-indica var. saboten Makino (Cactaceae) is
ies on PD is the clear evidence of a lower incidence of this
disease in tobacco smokers than in nonsmokers. Results of
neuroprotection studies in the C57BL/6 mouse provide evi-
dences that 2,3,6-trimethyl-1,4-naphthoquinone isolated
from tobacco protect against MPTP-mediated depletion of
neostriatal dopamine . In fact Fowler et al. using in vivo
positron emission tomography demonstrated lower MAO-A
and MAO-B activities in brains of smokers [53, 54].
One of the interesting outcomes of epidemiological stud-
HERBAL MEDICINES SHOWING MAO INHIBITION
FOR TREATING ANXIETY
ric disorders that affect all groups of the general population.
Anxiety disorders are among the most common psychiat-
In recent years much research has been done on the devel-
opment of synthetic anxiolytic drugs without dependence
potential, excessive sedative properties or other unwanted
side effect. However the available agents have numerous and
often serious adverse effects, including sedation, impaired
cognition, ataxia, aggression, sexual dysfunction, tolerance
and dependence. Herbal remedies have been shown to be
effective as alternative treatments, at least in mild to moder-
ate cases of anxiety. In this way, standardized preparations
of the root extract of Piper methysticum Forst. (Piperaceae),
termed kava-kava, has been introduced as a new no-synthetic
anxiolytic drug. Kava is a social and ceremonial herb from
South Pacific. Its pharmacological properties are postulated
to include blockade of voltage-gated sodium ion channels,
enhanced ligand binding to ?-aminobutyric acid (GABA)
type A receptors, diminished excitatory neurotransmitter
release due to calcium ion channel blockade, reduced neu-
ronal reuptake of noradrenaline, reversible inhibition of
MAO-B and suppression of the synthesis of the eicosanoid
thromboxane A2, which antagonises GABAA receptor func-
tion. Its actions are due to six major components called kava
lactones which appear to be more effective when used in
combination than individually . Also root bark of Pae-
onia suffruticosa Andrews (Ranunculaceae) is used as a
sedative agent to treat central stress. Its inhibition on MAO-
A is a bit less than on type B of the enzyme, this observation
could rationalize its application .
frequently used for the treatment of anxiety and insomnia.
Alkaloids such as jatrorrhizine and berberine are the MAO
inhibitors present in this plant. Inhibition of jatrorrhizine on
MAO-A was stronger than on MAO-B. Berberine exhibited
only a weaker MAO-A inhibition .
Rhizoma of Coptis chinensis Franch. (Berberidaceae) is
NATURAL COMPOUNDS IN PLANTS SHOWING
MAO INHIBITORY ACTIVITY
been isolated from the above mentioned plants. MAO inhibi-
tory activity is often responsible for their use in depression,
Parkinson or anxiety. IC50 values for these different types of
compounds are described in the following Tables 1-11.
In the present work, IC50 reported values were obtaining
from different experimental settings. It can explain the dif-
ferent IC50 reported for the same chemical compound found
in different plant, so values are not strictly comparable a
direct comparison must be conducted cautiously.
Many chemical compounds with different structures have
compounds common in certain families of flowering plants.
More than 3000 different types of alkaloids have been identi-
fied in a total of more than 4000 plant species. In their pure
form most alkaloids are colorless, nonvolatile, crystalline
solids. They also tend to have a bitter taste. Alkaloids show
great variety in their botanical and biochemical origin, in
chemical structure and in pharmacological action . The
chemical structures of alkaloids are extremely variable. Gen-
erally, an alkaloid contains at least one nitrogen atom in an
amine-type structure. Furthermore most alkaloids have one
or more of their nitrogen atoms as part of a heterocyclic ring.
Alkaloids are a group of naturally occurring chemical
Herbal Natural Products As a Source of Monoamine Oxidase Inhibitors Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20 2135
The interest in the alkaloids stems from the wide variety of
physiological effects they produce in humans and other ani-
mals (Table 1).
lated from P. negrum L. (Piperaceae) exhibited MAO inhibi-
tory activity . In aqueous extract of B. caapi Morton
(Malpighiaceae) were isolated and evaluated others ?-
carbolines and alkaloid glycosides containing azepino[1,2-
a]tetrahydro-?-carboline, resulting MAO inhibitors .
Further recent epidemiological studies have consistently
shown that natural pyrido-indole (?-carboline) alkaloids
identified and isolated from coffee: C. canephora Pierre ex
Froehner (Rubiaceae) or C. arabica L. (Rubiaceae) are good
inhibitors on MAO-A and MAO-B isozymes .
The alkaloid piperine, a cyclic six member amine, iso-
versible competitive inhibitors selective for MAO-A .
Related synthetic ?-carboline derivatives were also re-
lites widely spread throughout the plant kingdom. Phenolic
compounds are essential for the growth and reproduction of
plants, and are produced as a response for defending plants
against pathogens and stress in general. Chemically, they are
compounds with an aromatic ring linked to one or multiple
hydroxyl groups. They are an important group with numer-
ous substances, including structures from different moieties.
They include simple compounds, such as phenolic acids and
also more complex molecules such as flavonoids [21, 39, 45,
59, 60] (Table 2).
Phenolic or polyphenolic compounds are plant metabo-
nized as the pigments responsible for the colors of leaves,
especially in autumn. They are rich in seeds, citrus fruits,
olive oil, tea, and red wine. They are low molecular weight
compounds composed of two aromatic rings (A and B)
linked by an oxygenated heterocycle (C). They can be subdi-
vided according to their substituents into subclasses such as
flavanols, flavanones, flavonols, flavones, isoflavones Fig.
(1). This subdivision is primarily based on the presence (or
absence) of a double bond carbon-oxygen on position 4 of
the C (middle) ring, the presence (or absence) of a double
bond between carbon atoms 2 and 3 of the C ring, and the
presence of hydroxyl groups in position 3 of the C ring Fig.
(1). Also in the flavonoid structure, a phenyl group is usually
substituted at the 2-position of the pyrone ring whereas in
isoflavonoids, the substitution is at the 3-position .
Flavonoids are capable of modulating the activity of en-
zymes and affect the behaviour of many cell systems and
exerting beneficial effects on body. This property of flavon-
oids has aroused considerable interest. Many natural flavon-
oids (flavanols, flavanones, flavones, isoflavones and fla-
vonols) have been found to exert inhibitory MAO activity
(Table 3). Quercetin is the most potent compound isolated in
many species of plants: Calluna vulgaris L. (Ericaceae) ,
Melastoma candicum Blume (Melastomataceae) ,
Ginkgo biloba L. (Zingiberaceae) , Hipericum brasil-
iense  and Hipericum hircinum L. (Hypericaceae) ,
Cayratia japonica Thunb. (Vitaceae) , Morinda citrifolia
L. (Rubiaceae)  are only a few examples. This simple
Flavonoids are nearly ubiquitous in plants and are recog-
flavonol shows better results as MAO-A inhibitor with IC50
values of 0.01 μM although some authors describe also a
certain activity against MAO-B [62, 64-67]. It is difficult to
compare the IC50 values reported for the flavonoids because
assay conditions vary and not all studies give IC50 for stan-
dard compounds. In fact, as it can be observed in (Table 3),
very different values have been reported for quercetin which
has been isolated from different plants for different authors.
Methanol extract of the roots of Sophora flavescens showed
an inhibitory effect on mouse brain monoamine oxidase
(MAO). Bioactivity-guided isolation of the extract yielded
two known flavonoids, formononetin and kushenol F which
showed significant inhibitory effects on MAO in a dose-
dependent manner .
oids, even synthetic chemistry has tried to obtain new deriva-
tives. Indeed many synthetic flavonoids have demonstrated
excellent MAO inhibitory activity, showing also to be selec-
tive towards one or the other form .
Due to biological properties observed for natural flavon-
uted in fruit and vegetables. Today, interest in anthocyanin
pigments has intensified because of their possible health
benefits as dietary antioxidant. They differ other flavonoids
previously described in their oxidation state.
Anthocyanins are one class of flavonoids widely distrib-
L.) have long been used for improving visual acuity and
treating circulatory problems . More recently Dreisseitel
et al. described their effects on MAO enzymes .
Anthocyanin pigments of Bilberries (Vaccinum myrtillus
biogenetic precursors of open chain flavonoids and isofla-
vonoids, and are abundant in edible plants.
They are also key precursors in the synthesis of many
biologically important heterocycles such as benzothiazepine,
pyrazolines, 1,4-diketones, and flavones. Chemically, they
consist of open-chain flavonoids in which the two aromatic
rings are joined by a three carbon ?,?-unsaturated carbonyl
Chalcones (trans-1,3-diaryl-2-propen-1-ones) are the
ity of these type of molecules and is directed to behavioral
tests and assays on rat mitochondrial MAOs. In these studies
two chalcones were isolated from G. lutea L. (Gentianaceae)
which displayed competitive inhibitory properties against
MAO-B being more effective than on MAO-A as it is re-
ported in (Table 5) . These compounds have been the
basis for obtaining synthetic derivatives that have shown
interesting and selective MAO-B inhibitor activity in the
micro- and nano-molar ranges. To better understand the en-
zyme-inhibitor interaction and to explain the selectivity of
the most active compounds toward hMAO-B, molecular
modeling studies were carried out .
The literature is limited about the inhibitory MAO activ-
pounds with an enormous biological and pharmacological
interest [74, 75]. On one side, they are particularly important
Xanthones are a family of natural and synthetic com-
2136 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20
Viña et al.
Table 1. Inhibition of MAO Isoforms by Alkaloids of Different Plant Extracts
heptahydro-1H-azepino[1',2':1,2]pyrido[3,4-b]indol-5(2H)-one (banistenoside A)
heptahydro-1H-azepino[1',2':1,2]pyrido[3,4-b]indol-5(2H)-one (banistenoside B)
7-hydroxy-1-methyl-9H-pyrido[3,4-b]-indole (harmol) 0.018 --
7-methoxy-1-methyl-1,4,9-trihydro-3H-pyrido[3,4-b]indole (tetrahydroharmine) 0.074 >100
7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole (harmaline) 0.025 25.0
Banisteriopsis caapi 
9H-pyrido[3,4-b]indole (norharman) 6.5 4.7
Coffea arabica, Coffea canephora 
Piper negrum  49.3 91.3
Table 2. Inhibition of MAO Isoforms by Phenols of Different Plant Extracts
(2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol [(?)-epicatechin] 51.7 65.0
3,3',5,5',7,7'-hexol [(?)-procyanidin B2]
Banisteriopsis caapi 
Paeonia suffruticosa  54.6 42.5
trihydroxybenzoate (epigallocatechin gallate)
Rhodiola rosea  -- 4.8
(2R,3S)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol [(+)-catechin] -- 88.6
Uncaria rhynchophylla 
Table 3. Inhibition of MAO Isoforms by Flavonoids of Different Plant Extracts
Calluna vulgaris  18 --
Carytia japonica  2.8 90
Gentiana lutea  39.6 3.8
4’,5,7-trihydroxyflavonol (kaempferol) 0.7 --
4’,5,7-trihydroxyflavone (apigenin) 1 --
5,7-dihydroxyflavone (chrysin) 2 --
Ginkgo biloba 
Hipericum brasiliense  12 38
Herbal Natural Products As a Source of Monoamine Oxidase Inhibitors Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20 2137
(Table 3) contd….
4’,5,7-trihydroxyflavonol (kaempferol) 3.9 48
Hypericum hircinum  0.01 20
2-(3,4-Dihydroxyphenyl)-5,7- dihydroxy-3-[ [(2S,3R,4R,5R,6S)- 3,4,5-trihydroxy-6-methyl-2-
Melastoma candicum 
Mentha aquatica  955 288
3’,4',5,7-tetrahydroxyflavonol (quercetin) 3.2 31.7
Morinda citrifolia 
4’-methoxy-7-hydroxyisoflavone (formonetin) 21.2 11
2S-6-(2-isopropenyl-5-methyl-4-hexen-1-yl)-2’,4',5,7-tetrahydroxyflavanone (kushenol F)
Sophora flavescens 
Fig. (1). Skeleton and some subclasses of flavonoids.
in chemotaxonomy as systematic markers. On the other, they
have valuable pharmacological properties, plant extracts
containing xanthones are being used in traditional medicine
. Chemically xanthones are composed of planar six-
carbon conjugated ring systems. Carbons 1 to 4 and carbons
5 to 8 form 2 rings bridged through a carbonyl group and
oxygen Fig. (2). Each ring is connected in a fused formation
not allowing free rotation about carbon-carbon bonds. This
basic moiety attached with different side chains defines the
properties of different types of xanthone.
Fig. (2). Generic structure of xanthone.
Mangiferin, a natural xanthone C-glucoside, isolated
from Hypericum aucheri L. (Hypericaceae), showed excel-
lent MAO-A inhibitor activity in the nM range and low inhi-
bition against MAO-B isoform . Many hydroxyxan-
thones extracted from Chironia krebsii Griseb (Gentiana-
ceae) and Garcinia livingstonei T. Anderson (Clusiaceae)
have been also described as MAO inhibitors . In a study
of 21 natural xanthones isolated from different plant species
as Hipericum brasiliense L. (Hypericaceae) , Monnina
obtusifolia Kunth (Polygalaceae) , Monnina sylvatica
Schltdl. & Cham (Polygalaceae) , Halenia campanulata
Cuatrec. (Gentianaceae) , Gentiana lutea L. (Gentiana-
ceae) , Pentadesma reyndersii Spirlet (Clusiaceae) ,
Polygala virgata Thunb. (Polygalaceae) , Garcinia liv-
ingstonei T. Anderson (Clusiaceae), Garcinia gerrardii and
Chironia krebsii Griseb (Gentianaceae), the most potent bio-
active compound was the 1,5-dihydroxy-3-methoxy xan-
2138 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20
Viña et al.
Table 4. Inhibition of MAO Isoforms by Anthocyanins of Vaccinum myrtillus
Malvidin 22.1 18.7
Cyanidin 29.5 31.7
Peonidin 30.5 38.0
Petunidin 31.5 42.6
Vaccinum myrtillus 
Table 5. Inhibition of MAO Isoforms by Chalcones of Gentiana lutea
Gentiana lutea 
thone with IC50 values of 40 nM and 33 μM for MAO-A and
MAO-B respectively (Table 6) .
These results found for natural xanthones have prompted
the synthetic chemistry to produce new derivatives improv-
ing MAO inhibitory activity .
natural sources, especially green plants. They are an impor-
tant group of organic compounds that present a nucleus
structure of 1,2-benzopyrone. The pharmacological and bio-
chemical properties and therapeutic applications of simple
coumarins depend upon the pattern of substitution. Recently
studies pay special attention to the MAO inhibitory proper-
ties of both natural and synthetic coumarin derivatives [80-
85]. Coumarins with different ether chains at 7 position of
the benzopyrone nucleus, isolated from Dictamnus albus L.
(Rutaceae) and Zanthoxylum schinifolium L. (Rutaceae)
showed good MAO-A and MAO-B inhibitor activity [49,
86]. Also others furocoumarins (psoralen and isopsoralen)
and benzocoumarins, extracted respectively from Psoralea
corylifolia L. (Fabaceae) and Gentiana Lutea L. (Gentiana-
ceae), displayed inhibitory properties against MAO-B and
MAO-A, being the second most potent against MAO-B (Ta-
ble 7) [87, 47]. The mode of inhibition of both psoralen and
isopsoralen isolated from P. corylifolia towards MAO-A is
non-competitive in nature while MAO-B inhibition is com-
petitive in nature .
More than 300 coumarins have been identified from
verse chemicals structurally related to anthracene. Both natu-
ral and synthetic AQs have widespread applications
throughout industry and medicine. The term anthraquinone,
Anthraquinones (AQs) are a group of functionally di-
however, refers to one specific isomer, 9,10-anthraquinone
(IUPAC: 9,10-dioxoanthracene) wherein the keto groups are
located on the central ring. Although many different varieties
of anthraquinone by-products are present in the plant king-
dom, all of them posses the same molecular nucleus. The
natural emodin isolated from Polygonum multiflorum Thunb
(Polygonaceae) is a potent and selectively MAO-B inhibitor
 (Table 8).
Pyrans, Benzopyrans and Pyrones
pounds which present an unsaturated six membered ring con-
taining one oxygen atom and a ketone functional group.
There are two isomers denoted as 2-pyrone and 4-pyrone.
The 2-pyrone (or ?-pyrone) structure is found in nature as
part of the coumarin ring system. 4-Pyrone (or ?-pyrone) is
found in some natural chemical compounds such as
chromone, maltol and kojic acid.
Pyrones or pyranones are a class of cyclic chemical com-
variety of important hetero- and carbocyclic molecules 
and occur as structural subunits in numerous natural products
that exhibit a wide range of biological activity .
Pyrones are useful intermediates in the synthesis of a
[Piper Methysticum Forster (Piperaceae)], are generally con-
sidered to be responsible for its pharmacological activity in
humans and animals. They are highly lipophilic derivatives
of 5,6-dihydro-?-pyrone. The two most potent kava pyrones,
desmethoxyyangonin and methysticin display a competitive
inhibition pattern against MAO-B activity (Table 9) .
Kava pyrones, the major constituents of Kava-Kava
isolated from Morinda citrifolia L. (Rubiaceae), Noni Fruit,
exhibited similar inhibitory activities on MAO-A and MAO-
B enzymes .
Herbal Natural Products As a Source of Monoamine Oxidase Inhibitors Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20 2139
Table 6. Inhibition of MAO Isoforms by Xantones of Different Plant Extracts
1,5-dihydroxy-3-methoxyxanthone 0.04 33
1,8-dihydroxy-2,3,4,6-tetramethoxyxantone 15 15
1-hydroxy-3,5-dimethoxyxanthone 29 30
8-hydroxy-1,2,6-trimethoxyxanthone 19 14.7
1,2,6,8-tetrahydroxyxantone 24 25
1,3,7-trihydroxyxantone 8 61
Chironia krebsii 
Garcinia gerrardii  3.3 30
1,3,5-trihydroxy-4-(3’,7’-dimethyl-2’,6’-octen)xanthone 37.4 65.5
Garcinia livingstonei [64,78]
1,3,5,8-tetrahydroxyxantone 13 25
Gentiana lutea 
Halenia campanulata  25 25
Hypericum aucheri  0.041 0.001
3,5-dihydroxyxantone 4.5 100
Hypericum brasiliense 
1,3,5-trihydroxy-2-methoxyxantone 2.7 68
Monnina obtusifolia 
Monnina sylvatica  40 40
Pentadesma reyndersii  24 50
Polygala virgata  50 50
Table 7. Inhibition of MAO Isoforms by Coumarins of Different Plant Extracts
7-((R,E)-6'-hydroxy-3',7'-dimethylocta-2',7'-dienyloxy)coumarin 1.3 0.5
Dictamnus albus 
Gentiana lutea  >100 2.9
7H-furo[3,2-g]chromen-7-one (psoralen) 15.2 61.8
Psoralea corylifolia 
Zanthoxylum schinifolium  5.7 28.6
Table 8. Inhibition of MAO-B Isoform by Anthraquinone of Polygonum multiflorum Thunb (Polygonaceae)
Polygonum multiflorum  -- 35.4
2140 Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20
Viña et al.
Table 9. Inhibition of MAO Isoforms by Pyrans, Benzopyrans and Pyrones of Different Plant Extracts
PYRANS, BENZOPYRANS, PYRONES
Hypericum brasiliense  32.0 6.7
Hypericum polyanthemum  22.0 33.0
Morinda citrifolia  47.6 36.6
5,6-dihydro-4methoxy-6-styrylpyran-2-one (desmethoxyyangonin) -- 0.12
Piper methysticum (Kava-Kava) 
sults from the fusion of a benzene ring to a heterocyclic
pyran ring. In the Hypericum polyanthemum Klotzsch ex
Reichardt (Guttiferae) was isolated the 5-hydroxy-6-iso bu-
tyryl-7-methoxy-2,2-dimethylbenzopyrane which presents a
greater selectivity toward MAO-A and a moderate activity
against MAO-B (Table 9) .
Benzopyrane is a polycyclic organic compound that re-
Terpenes and Terpenoids
dary metabolites built up from five-carbon isoprene units (2-
methyl-1,3-butadiene) linked together most commonly in a
head-to-tail arrangement, but can be constructed in other
configuration with varying degrees of unsaturation, oxida-
tion, functional groups and ring closures, giving rise to a rich
diversity of structural classes, with novel skeletons being
continuous discovered. These modified hydrocarbons are
referred to as terpenoids, which are primarily found in a
wide variety of higher plants. The terpenes and terpenoids
are classified or grouped according to the number of iso-
prene units found in the parent nucleus, which include the
hemiterpenes (1), monoterpenes (2), sesquiterpenes (3),
diterpenes (4), sesterterpenes (5), triterpenes (6) and polyter-
penes (many units). Of these different major classes of ter-
penoids, the diterpenes are structurally most diversified, pos-
sessing at least 6 large structural groups, within which are
more than 20 sub-structural types. Biologically active com-
pounds are found in each class of the terpenoids, particularly
among the sesquiterpenes, diterpenes and triterpenes .
Three diterpenoids isolated from a dichloromethane extract
of the root of Salvia miltiorrhiza Bunge (Laminaceae), dis-
played a marked inhibitory effect on rat liver monoamine
oxidase, with a preference for the MAO-A (Table 10). The
compounds are different only in their degree of unsaturation
in rings A and D and thus seem of particular interest with
respect a preliminary understanding of structure-activity re-
lationship in this class of compounds Fig. (3). The data sug-
gest that an aromatic ring A and a dihydrofuran ring D are
more favorable for inhibition of MAO-A than a cyclohexane
ring with geminal methyl groups and tetrahydrofuran as ring
Terpenes are a large class of natural hydrocarbon secon-
Fig. (3). General structure of tanshinone-type diterpenoids.
rosea L. (Crassulaceae). It exhibit specific inhibitory activity
against MAO-B (Table 10) .
A monoterpen, rosiridin, was isolated from Rhodiola
from the fruits of Opuntia ficus-indica var. saboten. The
isolated compounds show weak MAO-A inhibitory activi-
ties, whereas their MAO-B inhibitory activities are stronger.
Citric acid methylesters, particularly dimethylester, are ma-
jor components in the MAO fraction found in the fruit of
Opuntia ficus-indica. Trimethyl citrate has been reported in
other plants, but not 1,3-dimethyl citrate and 1-monomethyl
citrate. The literature shows that these molecules including
1-methyl malate have MAO-B inhibitory activity, and that
other biological activities or industrial usages of these mole-
cules may be found through further investigation.
Three methyl citrate and one methyl malate were isolated
acid, shows the strongest activity. The methoxy group in
citric acid methylesters seems to be critical for the inhibitory
activity on MAO-B (Table 11) .
The citric acid monomethylester, the freest carboxylic
SCREENING OF MONOAMINE OXIDASE INHIBI-
TORS IN NATURAL EXTRACTS
covered and purified in a preparative, bioactivity-directed
approach involving substantial quantities of biological mate-
rial, manpower and time . As a consequence of the para-
digm shift in drug discovery towards screening of large
compound libraries in a highly automated high-throughput
In the past, bioactive natural products were typically dis-
Herbal Natural Products As a Source of Monoamine Oxidase Inhibitors Current Topics in Medicinal Chemistry, 2012, Vol. 12, No. 20 2141
Table 10. Inhibition of MAO Isoforms by Terpenoids of Different Plant Extract
Rhodiola rosea 
1,2-dihydro-1,6-dimethyl-(R)-phenanthro(1,2-b)furan-10,11-dione (15,16-dihydrotanshinone) 23.0 --
1,2,6,7,8,9-hexahydro-1,6,6-trimethyl- (R)-phenanthro(1,2-b)furan-10,11-dione(cryptotanshinone) 80.0 --
1,6-dimethyl- (R)-phenanthro(1,2-b)furan-10,11-dione (tanshinone I)
Salvia miltiorrhiza 
Table 11. Inhibition of MAO Isoforms by Esters of Opuntia ficus-indica
1-monomethyl citrate >2.0 0.19
1,3-dimethyl citrate >1.5 0.23
trimethyl citrate >1.5 0.61
Opuntia ficus-indica 
process, the search for natural product leads has come under
increasing pressure. Due to the importance of MAO inhibi-
tors, several methods have been developed for monitoring
MAO activity and its inhibitor screening. These methods
include HPLC  and capillary electrophoresis .
ing a HPLC assay which combines human recombinant
MAO-A, expressed as GST-fusion protein in yeast, with a
kinetic measurement of the conversion of kynuramine to 4-
MAO-A inhibitors in plants extracts can be detected us-
tracts, a facile capillary electrophoresis method has been
reported. The enzymatic reaction occurs at the capillary fol-
lowed by the electrophoresis separation of the reaction com-
pounds and detected by their UV absorbance .
For the screening of MAO-B inhibitors in natural ex-
MAO inhibitory activity are used in traditional medicine for
various CNS diseases such as depression, anxiety or Parkin-
son. Not many studies in vivo have been reported, however
the activity of the extracts or isolated components in vitro
has been extensively studied in many cases. Those extracts
used as antidepressants, A. catechu, C. longa or M. offici-
nalis herein described, have generally proven more selective
inhibitors of MAO-A. However, among those used for the
treatment of Parkinson, inhibitors of both MAO-A and
MAO-B isoforms have been found. Therefore, for others as
GT extract or B. caapi, the neuroprotective activity appears
to be independent of its MAO inhibitory activity. Extracts
used in the treatment of anxiety as those of P. suffruticosa or
C. chinensis show affinity for both isoforms.
A variety of plants containing chemical compounds with
MAO activity, alkaloids resulted potent and selective MAO-
A inhibitors while kava pyrones turned selective MAO-B
inhibitors. A wide variety of polyphenolic compounds show
activity against one of the two isoforms. Selectivity depends
on the nature and position of substituents.
Among naturally occurring chemical compounds with
cine alone or in combination for the treatment of these dis-
eases on the CNS. Therefore, natural compounds showing
MAO activity serves as basis for the chemical synthesis of
more potent and selective derivatives.
Results here described support the use of natural medi-
CONFLICT OF INTEREST
flicts of interest.
The author(s) confirm that this article content has no con-
Italy for financial support.
Giovanna Delogu thanks Fondazione Banco di Sardegna-
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Received: June 26, 2012 Revised: October 11, 2012 Accepted: October 11, 2012