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Research Article
Effect of Alkaloids Isolated from
Phyllodium pulchellum on Monoamine Levels and
Monoamine Oxidase Activity in Rat Brain
Lu Cai,1Chao Wang,1Xiao-kui Huo,1Pei-pei Dong,1Bao-jing Zhang,1Hou-Li Zhang,1
Shan-shan Huang,1Bo Zhang,2Sheng-ming Yu,3Ming Zhong,3and Xiao-Chi Ma1
1Coll ege of Phar macy, Dalian Med ical Unive rsity, D al ian 116 044 , China
2Department of Neurosurgery, e Second Aliated Hospital, Dalian Medical University, Dalian 116044, China
3Institute of Nationality Medicine in Guangxi, Nanning 530001, China
Correspondence should be addressed to Hou-Li Zhang; houlizh@.com and Bo Zhang; zhangbodl@.com
Received September ; Revised February ; Accepted March
Academic Editor: I-Min Liu
Copyright © Lu Cai et al. is is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Phyllodium pulchellum (P. pulchellum) is a folk medicine with a signicant number of bioactivities. e aim of this study was to
investigate the eects displayed by alkaloids fractions, isolated from the roots of P. pulchellum, on neurotransmitters monoamine
levelsandonmonoamineoxidase(MAO)activity.Six alkaloids, which had indolealkylamine or 𝛽-carboline skeleton, were obtained
by chromatographic technologies and identied by spectroscopic methods such as NMR and MS. Aer treatment with alkaloids of
P. pulchellum, the reduction of DA levels (.%) and -HT levels (.%) in rat brain was observed by HPLC-FLD. e eect of
alkaloids on the monoamines metabolism was mainly related to MAO inhibition, characterized by IC50 values of 37.35 ± 6.41 and
126.53 ± 5.39 𝜇g/mL for MAO-A and MAO-B, respectively. e acute toxicity indicated that P. pulchellum extract was nontoxic.
1. Introduction
Phyllodium pulchellum (P. p u l c h e l l u m ) Desv. (Leguminosae)
is a folk medicine distributed in the southern parts of
China, with a signicant number of bioactivities especially
for the central nervous system (CNS). P. p u l c h e l l u m exhib-
ited hypothermia and mild analgesic eects on rheumatoid
arthritis. Recently, many investigations suggested that the
ethanol extract of P. p u l c h e l l u m had signicant bioactivity
in vivo system of liver brosis [, ]. P. p u l c h e l l u m is widely
used in traditional medicine with no literature evidence
substantiating its safety. To optimize their safe use, it would
be urgent to study the safety and the chemical foundation.
Previous research had shown that chemical constituents
of P. pu l c h e l l u m included alkaloids, alcohols, and phenols. In
total alkaloids part, indolealkylamine (IAA) and 𝛽-carboline
type alkaloids were its main constituents [–]. To the
best of our knowledge, these alkaloids are regarded as the
promising plant-derived compounds to treat CNS illnesses,
duetotheiruniquecomplexnitrogen-containingstructures
to interact with diverse neuronal and molecular targets [].
IAA drugs were -hydroxytryptamine (-HT or serotonin)
analogs that mainly act on a variety of -HT receptors,
serotonin transporter, or even MAO enzyme that were highly
favorable molecular targets for treating depression, anxiety,
schizophrenia, and other psychiatric disturbances [, ].
Additionally, 𝛽-carbolines were naturally occurring alkaloids
that exhibited a wide range of psychopharmacological eects
due to their binding to benzodiazepine, imidazoline, sero-
tonin, and opiate receptors as well as monoamine oxidase
(MAO) activity inhibition [, ].
Dopamine (DA) and serotonin (-HT) play a major role
as neurotransmitters in the control and regulation of the
central nervous system. DA is one of the most important
excitatory neurotransmitters, involved in a variety of behav-
iors and brain functions, such as motor activity, cognition,
emotion, positive reinforcement, food intake, and endocrine
regulation []. Changes on DA transmission are associated
with Parkinson’s disease and schizophrenia []. -HT, as a
conventional neurotransmitter, is involved in the regulation
Hindawi Publishing Corporation
Evidence-Based Complementary and Alternative Medicine
Volume 2016, Article ID 6826175, 6 pages
http://dx.doi.org/10.1155/2016/6826175
Evidence-Based Complementary and Alternative Medicine
T : E e c t s o f P. pulchellum alkaloids administered p.o. in mice.
Dose (mg/kg) Obituary/total animals Mortality (%) Mortality latency (h) LD50 (mg/kg)
/ —
/ >, <
/ >, <
/ >, <
/ >, <
of mood, sleep, memory, learning, and sexual behavior as
a crucial ne-tuner of normal and pathological processes
[]. Alterations in -HT transmission are related to some
neurological and psychiatric illness including migraine, hal-
lucinations, anxiety, and depression [].
Monoamine oxidases (MAOs) are mitochondrial bound
isoenzymes which catalyze the oxidative deamination of
monoamine neurotransmitters, including -HT, histamine,
and catecholamines (dopamine, noradrenaline, and
adrenaline). MAO is classied into two types (Aand B),
according to their sensitivity towards specicity substrates
and inhibitors. MAO-A shows a higher anity for -HT
and noradrenaline and is selectively inhibited by clorgyline,
whereas MAO-B preferentially deaminates phenylethylamine
and benzylamine and is selectively inhibited by l-deprenyl or
pargyline. Dopamine is oxidized by both forms of the enzyme
in most species []. MAO-A inhibitors have proven to be
eective in the pharmacological treatment of depression, and
further developments have provided reversible inhibitors
of MAO-A, which oer antidepressant activity without
the serious side eects of the earlier inhibitors. On the
other hand, selective inhibitors of MAO-B have found a
therapeutic role in the treatment of Parkinson’s disease [].
Considering the presence of indolealkylamine and 𝛽-
carboline alkaloids compounds in P. p u l c h e l l u m and the
previous eects described for these alkaloids on the CNS, it
becomes relevant to investigate the eects of fractions of P.
pulchellum on monoamines metabolites and MAO activity.
In order to give vital guidance to uses and further develop-
ments of P. p u l c h e l l u m , the investigation regarding chemical
constituents of P. p u l c h e l l u m alkaloid and its inuences of
monoamine levels and monoamine oxidases (MAO-A and
-B) was carried out in the present paper.
2. Results and Discussion
2.1. Acute Toxicity. e results of the acute toxicity were
shown in Table . ere was a regular dose-dependent
increase in mortality and decrease in mortality latency in
both sexes of mice aer the administration of P. p u l c h e l l u m
extract. e rst mouse died between and h aer
injection of the mg/kg dose of the extract, and the
maximum frequency of death occurred at mg/kg. e
no-observed–adverse-eect (NOAEL) dose for the extract
wasmg/kg,themaximumtolerateddose(MTD:highest
dose at which the mice recovered completely) was assumed
to be between mg and mg/kg, and the single
dose LD50 was mg/kg (% condence limit: –
mg/kg). e symptom of weight loss was observed
5
1
6
2
34
1,000
875
750
625
500
375
250
125
−100
0.3 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0 45.0 50.0
(min)
(mAU)
WVL: 210 nm
F : Chromatogram of total alkaloids of Phyllodium pulchellum
with six alkaloids (–) indicated ( nm).
during the later stages of the experiment. e histological
analysis showed an absence of alterations in all organs
examined (results were not shown).
P. pu l c h e l l u m is widely used traditionally in the southern
parts of China with no literature evidence substantiating
its safety, so it is necessary to evaluate the toxicity of this
medicinal herb. In the present study, the LD50 of P. p u l c h e l l u m
extract was mg/kg , based on the classication of Loomis
and Hayes [], namely, that substances with LD50 between
and mg/kg bodyweight are regarded as being
practically nontoxic. However, some mild adverse eects such
as dizziness, trembling, crouching, and sluggishness were
observed, and the eect was reversible within min and
vanished aer hr.
2.2. Chemical Constituents. e total alkaloids were obtained
as the CHCl3extracted materials from the hydrochloric acid
water extract of the roots of P. p u l c h e l l u m with the content
of .%. It was also analyzed by HPLC subjected to a RP
C column at ∘CwithDADdetection.emobilephase
was comprised of water (solvent A) and acetonitrile (solvent
B) both acidied with .% CF3COOH using a gradient
manner: % B– % B for min, at .mL/min. HPLC
chromatograms of total alkaloids were recorded with UV
detection at nm, as shown in Figure .
Totally, six alkaloids were obtained by various chroma-
tography techniques (Figure ). ey were elucidated as N,N-
dimethyltryptamine (), -methoxy-N,N-dimethyltrypta-
mine (), N-methyltetrahydrocarboline (), -methoxy-
N-methyltetrahydrocarboline (), tryptamine (), and N-
methyl--indoylmethanamine ()fromtheirspectroscopic
data upon comparisons with values reported in the literature
Evidence-Based Complementary and Alternative Medicine
12 3
45 6
4
4a
5
6
7
7a
89
10
11
N
N
H
3
2
1
4
4a
5
6
7
3
2
1
7a
89
10
11
N
N
H
H3CO 4
56
7
3
2
2a
5a6a
8
99a
10
1
N
N
H
4
56
7
2
2a
5a
6a
8
99a
10
1
N
N
H
H3CO 4
4a
5
6
7
3
2
1
7a
89
N
H
NH24
4a
5
6
7
3
2
1
7a
8
9
N
H
NH
F : e alkaloids –isolated from the roots of P. pulchellum.
T : Eects on monoamine neurotransmitters and their metab-
olites of the rat brain aer administration of P. pulchellum alkaloids
( mg/kg).
Control (𝑛=8)
(ng/g tissue)
Tre a ted (𝑛=8)
(ng/g tissue)
-HT (.%) . ±. . ±.∗
-HIAA (.%) . ±. . ±.∗∗
Dopamine (.%) . ±. . ±.∗∗
DOPAC (.%) . ±. . ±.∗∗
Results are mean ±SEM (standard error of the mean). Statistical signicance:
∗𝑃<0.05and ∗∗𝑃<0.01compared with control (Student’s 𝑡-test).
[]. According to the structure characteristics, six alkaloids
can be divided into two dierent structure styles: compounds
,,,andbelonged to indolealkylamine and compounds
and were 𝛽-carboline alkaloids.
2.3. HPLC-FLD Analysis. In the present study, the mono-
amine levels of DA and -HT and their main metabolites
(DOPAC and -HIAA) were quantied by HPLC-FLD in
brain of rats aer treatment with alkaloids of P. p u l c h e l l u m .
e concentrations of DA, DOPA, -HT, and -HIAA in
experimental group were signicantly dierent from the
control group (Table ). In dopaminergic system, a decrease
of .% in DA levels and a decrease in the levels of
metabolites DOPAC (.%) were observed. e ratios of
metabolites to monoamines were evaluated to estimate the
activity of brain monoamine metabolism []. ere was
a signicant decrease in DA concentration associated with
an increased DOPAC/DA ratio of this monoamine aer the
administration of P. p u l c h e l l u m . ese data indicated that P.
pulchellum may cause alterations in DA and metabolites levels
in rat brain.
In serotonin system, there was a signicant reduction
in the -HT levels (.%) following the decreased levels
of -HIAA (.%). e ratio -HIAA/-HT is frequently
employed as a serotonin metabolism indicator, since it
establishes the -HT consumption and the formation of its
metabolitesproduct.Inthisassay,whenratsreceivedP. p u l -
chellum alkaloids, the serotonin turnover ratio (-HIAA/-
HT) was decreased from . to ., which indicated that
alkaloids attenuated the monoamines metabolism in this
brain area.
e main chemical constituents of P. p u l c h e l l u m were
alkaloids which had indolealkylamine skeleton and -
methoxy-N,N-dimethyltryptamine (-MeO-DMT) as major
substances. e indolealkylamine alkaloids showed a rela-
tively high oil/water partition coecient, suggesting that the
alkaloids may easily penetrate various lipoprotein barriers
including the blood brain barrier. As shown previously [,
], -MeO-DMT signicantly accumulates in many organs
(e.g., liver, kidney, and brain) in dierent animal models.
e brain concentration of -MeO-DMT is about .-fold
higher than that in blood at min aer administration, and
the drug is widely distributed in dierent rat brain regions
including cortex, thalamus, hippocampus, basal ganglia,
medulla, pons, and cerebellum.
e alkaloids from P. p u l c h e l l u m produced a short-lived
decrease in locomotor activity and investigatory behavior in
rats aer oral administration. e hypoactivity eect could
be attributed to the presence of indolealkylamine (IAA)
alkaloids in P. p u l c h e l l u m ,becauseIAAcompoundswere-
HT analogs that mainly act on a variety of -HT receptors or
serotonin transporters, which have been used in social and
religious cultures throughout history [].
2.4. MAO. e eect of alkaloids isolated from P. p u l c h e l l u m
onMAOwasevaluatedinmitochondrialfractionsfrom
rat brain. As shown in Figure , P. p u l c h e l l u m alkaloids
Evidence-Based Complementary and Alternative Medicine
100
MAO-A activity (% of control)
80
60
40
20
0
−2−10 1 2 3
MAO-B activity (% of control)
100
80
60
40
20
0
−2−10123
log[alkaloids (𝜇g/mL)] log[alkaloids (𝜇g/mL)]
F : Eects displayed by P. pulchellum on MAO-A and MAO-B activity. P. pulchellum alkaloid was tested in ten dierent concentrations
ranging from . to 𝜇g/mL. e degree of inhibition IC50 was assessed by a sigmoidal dose-response curve. Each point represents the
mean ±SMD of the sigmoidal regression for three independent determinations.
signicantly inhibited both MAO-A and MAO-B activity in a
concentration-dependent pattern. e IC50 values calculated
for alkaloids (37.35 ±6.41 and 126.53±5.39𝜇g/mL for MAO-
A and MAO-B, resp.) indicated high potency against MAO-
A. Additionally, regarding the activity against MAO-A, the
tested extracts displayed maximum inhibition above % in
the highest concentrations evaluated.
e inhibition observed on MAO activity is in agreement
with the reduction in DOPAC levels in rat brain, since
DA is a nonselective substrate for MAO-A and MAO-B,
beingconvertedtoDOPACbybothenzymes.eselective
inhibition on MAO-A is in agreement with the reduction in
-HIAA levels, since -HT is a selective substrate for MAO-A.
In addition to indolealkylamine alkaloids, we also isolate
and identify the 𝛽-carboline alkaloids: compound (N-
methyltetrahydrocarboline) and compound (-methoxy-
N-methyltetrahydrocarboline). So far, studies of the activity
of the compounds have not been reported in the literature;
however, reports were found for chemically related alkaloids
such as harmine, harmaline, and tetrahydroharmine, which
are potent and reversible inhibitors of MAO [, ]. ere-
fore, the alkaloids present in the aqueous extract from P.
pulchellum could play a role in the MAO inhibition.
In conclusion, the present study demonstrates that
aqueous exact of the root of P. p u l c h e l l u m was nontoxic.
e main chemical constituents were alkaloids which had
indolealkylamine or carboline skeleton and -methoxy-
N,N-dimethyltryptamine and N,N-dimethyltryptamine were
major substances. e alkaloids seem to act on -HT and DA
systems in rat brain, aecting the monoamines metabolism
and MAO activity.
3. Material and Methods
3.1. Chemicals. -Hydroxyquinoline, kynuramine dihydro-
bromide, selegiline, and clorgyline were obtained from Sigma
(St. Louis, MO, USA). All other reagents were of analytical
grade.
3.2. Plant Material. e roots of P. p u l c h e l l u m were col-
lected in Gongcheng, Guangxi, China, in August and
identied by Chief Physician Bin Dai from the Institute of
Nationality Medicine in Guangxi. A voucher specimen has
been deposited at the Herbarium of Institute of Nationality
Medicine in Guangxi (S-).
3.3. Animals and Treatment. Wistar rats (200 ± 20g) and
mice (20 ± 2 g) were purchased from the Laboratory Animal
Center of Dalian Medical University. Before the experiments,
the rats were allowed one-week acclimation period in the
animal quarters under air conditioning (∘±∘C, humidity
–%) and an automatically controlled photoperiod of h
light daily, fed with standard rodent chow and tap water ad
libitum. e experimental procedures were carried out in
accordance with the National Institutes of Health Guide for
theCareandUseofLaboratoryAnimalsandwereapproved
bytheAnimalCareandUseCommitteeoftheDalianMedical
University. Aer acclimatization, the rats were randomly
divided into two groups (𝑛=8). e alkaloids isolated
were dissolved in distilled water for oral administration in
treated groups at the dosages of mg/kg; the control animals
received an equivalent volume of the vehicle. Half an hour
aer administration, animals were sacriced by decapitation
and brains were immediately removed, washed in ice-cold
isolationmedium,andstoredat−∘Cuntilanalyzed.
3.4. Acute Toxicity. Acute toxicity was tested using a variation
ofthemethoddescribedbyLitcheldJr.andWilcoxonin
[]. Mice were randomly divided into six groups with ve
female mice and ve male mice in each group. e P. p u l c h e l -
lum sample was extracted by decoction and administered by
gavage (p.o.) at single doses of , , , , and
mg/kg body weight, while normal saline equivalent to
the highest volume of the extract given was administered
to the control group. e general behavior of the mice was
continuously monitored for h aer dosing, periodically
during the rst h (with special attention given during the
Evidence-Based Complementary and Alternative Medicine
rst h) []. e mice were further observed for up to
days aer treatment and any signs of toxicity and deaths were
recorded.Atdays,themicewerekilledandhistological
analysis was made of the following organs: heart, kidney,
lung, liver, spleen, duodenum, pancreatic, bladder, brain, and
genitals.
3.5. Extraction and Isolation. e air-dried and powdered
roots ( kg) of P. p u l c h e l l u m were ultrasonically extracted
with hydrochloric acid water solution (pH -) ( Hz ×h
×). Aer the dregs were ltrated, the aqueous solution was
subjected to strongly acidic cation-exchange resin column
chromatography and eluted with water till neutrality (pH
). When the resin was treated with ammonia water, it
was extracted by % ethanol. Aer evaporation of ethanol
in vacuo, the aqueous residue of the ethanolic extract was
dilutedwithwaterandthenpartitionedwithCHCl
3.e
CHCl3extract ( g) was obtained as the total alkaloids
and subjected to column chromatography on silica gel with
petroleum ether-acetone ( : - : ) to aord ve fractions
(F–F). Subfraction F (. g) was further isolated on RP-
column and nally puried by preparative HPLC (mL/min,
nm, CH3CN-H2O-CF3COOH ( : : ., v/v/v)) to
give compounds (. mg, Rf . min) and (. mg, Rf
. min). Compounds (. mg, Rf . min) and (. mg ,
Rf . min) were puried from subfraction Fr by pre-HPLC
( mL/min, nm, CH3CN-H2O-CF3COOH ( : : .,
v/v/v)), and compounds (. mg, Rf . min) and (. mg,
Rf . min) were isolated form Fr by pre-HPLC ( mL/min,
nm, CH3CN-H2O-CF3COOH ( : : ., v/v/v)).
3.6. HPLC-FLD Analysis. Detections of the levels of DOPA,
DA, -HT, and -HIAA in brain tissues of mice were carried
outbyHPLC-FLD[].ebraintissuewasputintochilled
tubes, homogenized in . 𝜇L perchloric acid (. M) on ice.
e homogenates were centrifuged at , ×gformin
and 𝜇L of the supernatant was ultraltrated for another
min. e instrument parameters used for HPLC-FLD
are as follows: Waters chromatographic system, Diamonsil
ODS column (. mm ×mm),mobilephase:methanol-
buer (buer: . mol NaH2PO4,mmolsodiumoctane-
sulfonate, pH .); ow rate: . mL/min; injection volume:
𝜇L; column temperature: ∘C. Excitation and emission
of the uorescence detector were set to and nm,
respectively. e area of peak amplitude was detected and
the level of detecting index calculated by a standard curve.
e tissue levels of monoamine were expressed in terms of
nanograms per gram of tissue. Student’s 𝑡-test was employed
for comparisons between control and treated groups. e
results were expressed as mean ±SEM (standard error of the
mean). When the 𝑃value was <. (∗), the dierence was
considered signicant.
3.7. Preparation of Brain Mitochondria. Wistar rats were
killed by decapitation. Brains tissues were immediately
removed and were mechanically homogenized in a Potter-
Elvehjem tissue grinder in vol of the ice-cold sodium phos-
phate buer ( mM, pH .) containing mM sucrose.
en, the homogenate was centrifuged at ×gformin
at ∘C to remove nuclei and cell debris. e mitochondrial
fraction was obtained by further centrifugation at , ×g
for min at ∘C and resuspended in PBS buer (pH .).
Protein concentration was determined by the Lowry method
[].
3.8. MAO Inhibition Assay. Monoamine oxidase inhibition
assays were carried out with uorescence based method (end-
point lecture), as previously described [, ]. e substrate
used for the assay was kynuramine, which is nonuorescent
until it undergoes oxidative deamination by MAO resulting
in the uorescent metabolite -hydroxyquinoline. Product
formation was quantied by comparing the uorescence
emission of the samples to that of known amounts of authen-
tic metabolite -hydroxyquinoline. Reactions were carried
out in black polystyrene -well microtiter plates in a nal
volume of 𝜇L. For the MAO-A inhibition assays, the
wells containing 𝜇L of PBS (pH .), 𝜇Lofpargyline
𝜇M (to get a nal concentration of nM), 𝜇Lofthe
sample solution prepared in PBS and DMSO (to get a nal
concentration of % DMSO), and 𝜇Lofthemitochondrial
suspension (to get a nal protein concentration of . mg/mL)
were preincubated at ∘C for min. e MAO-B inhibition
assays were performed in the same way as that of the MAO-A
incubations, except by the use of 𝜇Lofclorgyline(𝜇M)
to replace the pargyline solution. e assay was started
by addition of 𝜇L kynuramine (nal concentration of
𝜇M)andwasstoppedbyadditionof𝜇L of M NaOH
solution min later. e uorescence intensity was detected
with excitation at nm and emission at nm using
a uorescence spectrometer. Alkaloids were tested in ten
dierent concentrations ranging from . to 𝜇g/mL. Data
analysis was performed with GraphPad Prism . soware.
e degree of inhibition IC50 was assessed by a sigmoidal
dose-response curve.
4. Conclusion
e alkaloids were main chemical constituents of aqueous
exact of the root of Phyllodium pulchellum.Structureanalyses
indicated that the alkaloids have indolealkylamine or carbo-
line skeleton and -methoxy-N,N-dimethyltryptamine and
N,N-dimethyltryptamine were major substances. e acute
toxicity indicated that the alkaloids extract was nontoxic. e
alkaloids seem to act on -HT and DA systems in rat brain,
aecting the monoamines metabolism and MAO activity.
Competing Interests
e authors declare that they have no competing interests.
Authors’ Contributions
Lu Cai and Chao Wang contributed equally to this work.
Acknowledgments
is work was supported by the National Natural Science
Foundation of China (nos. and )
Evidence-Based Complementary and Alternative Medicine
and Liaoning Provincial Natural Science Foundation
().
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