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Research Paper

Journal of Pharmacy
And Pharmacology

Serotonergic mechanisms are involved in
antidepressant-like effects of bisbenzylisoquinolines
liensinine and its analogs isolated from the embryo of
Nelumbo nucifera Gaertner seeds in mice
Yumi Sugimotoa,b, Katsumi Nishimurab, Atsuko Itohb, Takao Tanahashib, Hiroshi Nakajimac,
Hideo Oshirod, Shujian Sund, Takahiro Todae and Jun YamadaeaDepartment of Pharmacology, Faculty of Pharmaceutical Sciences, Yasuda Women’s University, Hiroshima, bDepartment of Organic Chemistry,
Kobe Pharmaceutical University, Kobe, cResearch Center for Industry Innovation, Osaka City University, dShanghai University of Traditional Chinese
Medicine, Osaka and eLaboratory of Pharmacology, Department of Clinical Pharmacy, Yokohama College of Pharmacy, Yokohama, Japan

Keywords
antidepressant-like effects; isoliensinine;
Liensinine; neferine; Nelumbo nucifera
Gaertner
Correspondence
Yumi Sugimoto, Department of Pharmacology,
Faculty of Pharmaceutical Sciences, Yasuda
Women’s University, 6-13-1, Yasuhigashi,
Asaminami-ku, Hiroshima 731-0153, Japan.
E-mail: yumisugi03@gmail.com
Received March 12, 2015
Accepted July 6, 2015
doi: 10.1111/jphp.12473

Abstract
Objectives We attempted to ascertain if bisbenzylisoquinoline alkaloids,
liensinine and isoliensinine from Nelumbo nucifera Gaertner have antidepressantlike effects and compare the effects with those previously obtained by their analogue neferine.
Methods Using mice, the forced swimming test (FST) was carried out after treatment with liensinine, isoliensinine and neferine.
Key findings Liensinine and isoliensinine elicited antidepressant-like effects inmice after the FST. Anti-immobility effects of liensinine and isoliensinine wereantagonized by the 5-hydroxytryptamine1A (5-HT1A) receptor antagonist WAY
100635, but not by the α1-adrenoceptor antagonist prazosin. The anti-immobility
effects of liensinine, isoliensinine and neferine were blocked by pretreatment withp-chlorophenylalanine (PCPA), which depletes serotonin (5-HT).
Conclusions These data suggest that liensinine and isoliensinine from Nelumbo
nucifera Gaertner have antidepressant-like effects and that antidepressant-like
effects of liensinine and its analogues are closely related to serotonergic
mechanisms.

Introduction
Natural compounds that may be effective for the treatmentof psychiatric disorders such as depression and anxiety havebeen isolated from medicinal plants.[1] Nelumbo nucifera
Gaertner is distributed in all parts of the world. Several
parts of this plant (e.g., leaves, flowers, rhizomes) containuseful compounds such as flavonoids and alkaloids.[2]Embryos of the seeds of Nelumbo nucifera Gaertner areused widely as Chinese traditional medicines presenting
sedative, antipyretic and hypothermic effects in humans.[3]Embryos of these seeds contain the bisbenzylisoquinoline
alkaloids neferine, liensinine or isoliensinine (Figure 1).[4–6]
However, the detailed effects and mechanisms ofpharmacologic action of bisbenzylisoquinoline alkaloids onthe central nervous system (CNS) have not been investi-

gated. Previously, we reported that the major alkaloid
neferine reduces locomotor activity, elicits hypothermia andpotentiates thiopental-induced sleep in mice.[7] Furthermore, we reported that neferine has anxiolytic effects
similar to those of diazepam in the elevated plus maze
test.[7] In addition, neferine was shown to haveantidepressant-like effects in mice when using the forced
swimming test (FST).[8]It has been reported that liensinine has anti-arrhythmic
effects in rats as a result of the blockade of influx of Ca2+and Na+.[9] Isoliensinine has been shown to inhibit
bleomycin-induced pulmonary fibrosis in mice.[10] Recently,
we found that liensinine and isoliensinine reduce locomotor
activity (i.e., have sedative effects) in mice.[11] These results© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

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Bisbenzylisoquinoline against depression

Yumi Sugimoto et al.

Animals

MeO
1 N

O

H

Male ICR mice (25–30 g, 5 weeks) were purchased fromSLC Japan (Shizuoka, Japan). Mice had free access to foodand water and were maintained on a 12-h dark–light cycle
in a room with controlled temperature (23 ± 1°C) andhumidity (55 ± 5%).

Me

HO
12
OR1
Me

H
N 1′

7′ OR2Forced swimming test

6′ OMeR1 = R2 = Me: neferine
R1 = H, R2 = Me: liensinine
R1 = Me, R2 = H: isoliensinine
Figure 1 Chemical structures of alkaloids from the embryos of theseeds of Nelumbo nucifera Gaertner.

raise the possibility that liensinine and isoliensinine may
have antidepressant effects similar to those of neferine.
However, there are differences in the involvement of adenosine triphosphate-binding cassette transporters in theabsorption of these alkaloids.[12] Thus, it is not clear
whether liensinine and isoliensinine show antidepressantlike effects as observed with neferine treatment. Hence, we
studied the effects of liensinine and isoliensinine on immobility in the FST and compared these effects with those ofneferine. Further, the involvement of serotonergic andnoradrenergic systems in antidepressant-like effects ofliensinine, isoliensinine as well as neferine was examined.

Materials and Methods
Experiments were carried out in accordance with the
Guiding Principles for the Care and Use of Laboratory
Animals approved by the Japanese Pharmacological Society.
The study protocol was approved by the Ethics Committee of the University of Yasuda Women’s University (protocol number 1412).

Extraction and isolation fromplant materials
Embryos of the seeds of Nelumbo nucifera Gaertner(Nelumbonaceae, Chinese folk medicine ‘Lian zi xin’) collected in China were purchased from the Longhua Hospital(Shanghai University of Traditional Chinese Medicine,
Shanghai, China). A voucher specimen (KPUY-031) isdeposited in the laboratory of Kobe Pharmaceutical University. Liensinine, isoliensinine and neferine were isolated andidentified from the embryos of the seeds of Nelumbo
nucifera Gaertner according to the method described in ourprevious report.[13] Isolated bisbenzylisoquinoline alkaloids
were prepared as the hydrochloride salt.
2

The FST was carried out according to the methods
described by Porsolt et al.[14] and our previous reports.[8,15]
Each mouse was placed in a 25-cm glass cylinder (diameter,
10 cm) containing 10 cm of water at 23 ± 1°C. Immobility
was recorded during a 6-min swimming test. A mouse wasjudged to be immobile if it floated and its hindlimbs were
immobile, and if only small movements of the forepaws
were made to keep its head above water.

Drug treatment
N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N(2pyridinyl)cyclohexanecarboxamide maleate (WAY 100635),
imipramine HCl, prazosin HCl and p-chlorophenylalanine(PCPA) methyl ester HCl were obtained from SigmaAldrich (St Louis, MO, USA). All drugs were dissolved inphysiologic (0.9%) saline and administered via the intraperitoneal route. The volume of administration was
0.1 ml/10 g body weight. Mice in the control group received
saline. WAY 100635 was given 30 min before administration of liensinine or isoliensinine. PCPA (300 mg/kg,
intraperitoneally) was given 72, 48 and 24 h before administration of liensinine, isoliensinine and neferine. The FST
was carried out 30 min after treatment with liensinine,isoliensinine and neferine.

Statistical analyses
Results are mean ± standard error (SE) of five to nine micein the behavioural studies. Differences between groups ofanimals treated with 0.9% saline or drugs alone wereassessed using one-way analysis of variance (ANOVA) followed by the Dunnett’s multiple comparison post-hoc test.
Other data were analyzed by two-way ANOVA. Pairwise
follow-up comparisons of individual treatment groups wereanalyzed by the Tukey’s multiple comparison post-hoc test.

Results
Effects of liensinine, isoliensinine andneferine on the immobility time of mice
Figure 2 shows the effects of liensinine, isoliensinine,
neferine and imipramine on the time of immobility ofmice. Anti-immobility effects of liensinine, isoliensinine© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

Yumi Sugimoto et al.

Bisbenzylisoquinoline against depression

250
**

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**

150

**

100
50
0

Immobility time (s)Immobility time (s)

250

**
**

150
100
50
0

Saline102550
Liensinine (mg/kg)

Saline102550Isoliensinine (mg/kg)

250
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150
100
50

Immobility time (s)250Immobility time (s)

200

**

200

**
150

**

100
50
0

0
Saline1025
Neferine (mg/kg)

50

Saline102550Imipramine (mg/kg)

Figure 2 Effects of liensinine, isoliensinine, neferine and imipramine on immobility in the forced swimming test in mice. Results are the mean ± SE
(n = 6–9). *P < 0.05, **P < 0.01. White bar graph shows the saline-treated group. Striped bar graph shows the respective drug-treated group.

and neferine were examined 30 min after administration
based on previous studies on its sedative effects and anxiolytic effects of neferine.[7,11] Liensinine elicited apparent
antidepressant-like effects at 10, 25 and 50 mg/kg.
Isoliensinine elicited significant anti-immobility effects at
25 and 50 mg/kg. Neferine elicited significant antiimmobility effects at 25 and 50 mg/kg. Imipramine produced significant anti-immobility effects at 10, 25 and
50 mg/kg.

Effects of WAY 10063 on liensinine andisoliensinine-induced anti-immobility effects
in mice
Figure 3 demonstrates the effects of 5-HT1A receptor
antagonist WAY 106335 on the antidepressant-like effects
elicited by liensinine and isoliensinine. WAY 100635 (0.5
and 1 mg/kg) significantly attenuated the anti-immobility
effects of liensinine and isoliensinine. Doses of WAY 100635
were chosen based on information on how they block the
5-HT1A receptors.[16,17]

Effects of PCPA on liensinine, isoliensinineand neferine-induced anti-immobility
effects in mice
Figure 4 shows the effect of PCPA (which depletes 5-HT)
on bisbenzylisoquinolines-induced anti-immobility effects.

PCPA significantly attenuated the anti-immobility effects ofliensinine, isoliensinine and neferine. Previous reportssuggested that the treatment with PCPA in this study
could decrease brain 5-HT levels (over 60%), whereas
noradrenaline and dopamine levels are not altered.[18,19]

Effects of prazosin on liensinine,isoliensinine and neferine-induced
anti-immobility effects in mice
Effects of the α1-adrenoceptor antagonist prazosin on
the antidepressant-like effects elicited by liensinine,isoliensinine and neferine (Figure 5). Prazosin did not affectanti-immobility effects of three alkaloids.

Discussion
Recently, a multitude of pharmacologic effects ofbisbenzylisoquinoline alkaloids from the embryos of theseeds of Nelumbo nucifera Gaertner have been reported.[2]Pharmacologic analyses of bisbenzylisoquinoline alkaloid
neferine in mice revealed that it has sedative, anxiolytic
effects and, using the FST, it has antidepressant-like
effects.[7,8] Moreover, it was reported that neferine improves
anti-amnesic effects in rats.[20]We reported that the other alkaloids from the embryos ofthe seeds of Nelumbo nucifera Gaertner liensinine andisoliensinine have sedative effects in mice.[11] However, it© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

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Bisbenzylisoquinoline against depression

Yumi Sugimoto et al.

(a)

Saline300
Immobility time (s)

###

#

200
150

***

100

###
#

200
150

***

100
50

50
0

Isoliensinine

250
Immobility time (s)Liensinine

250

Saline

(b)
300

0

0
0.5
1
WAY 100635 (mg/kg)

0

0.5
1
WAY 100635 (mg/kg)

Figure 3 Effects of WAY 100635 on liensinine and isoliensinine-induced anti-immobility in mice. Results are the mean ± SE (n = 5). (a) Liensinine,(b) Isoliensinine. WAY 100635 was injected 30 min before liensinine (50 mg/kg) or isoliensinine (50 mg/kg). ***P < 0.001 vs saline of the respective
group. #P < 0.05, ###P < 0.001 vs saline + liensinine or isoliensinine-treated group.

(a)

(b)

(c)
SalineLiensinine

250

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200

***

150
100
50
0

SalinePCPASalineIsoliensinine
###

250
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***

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100
50
0

Saline300
Immobility time (s)

300

300
Immobility time (s)Immobility time (s)SalinePCPA

Neferine
###

250
200

***

150
100
50
0

SalinePCPA

Figure 4 Effects of p-chlorophenylalanine (PCPA) on bisbenzylisoquinolines-induced anti-immobility in mice. Results are the mean ± SE (n = 5–7).
(a) Liensinine, (b) Isoliensinine, (c) Neferine. PCPA (300 mg/kg) was given 72, 48 and 24 h before liensinine (50 mg/kg), isoliensinine (50 mg/kg) andneferine (50 mg/kg). ***P < 0.001 vs saline of the respective group. ###P < 0.001 vs saline + respective alkaloid-treated group.

was not clear whether liensinine and isoliensinine are
effective against depression. Therefore, we examined ifliensinine and isoliensinine have antidepressant-like effects
in mice.
In this study, the typical antidepressant imipramine elicited dose-dependent anti-immobility effects, which reveals
that the FST in this study can be used for evaluation ofantidepressant effects. Liensinine and isoliensinine elicited
significant anti-immobility effects in mice. Liensinine
showed significant antidepressant effects at lower doses
than those of isoliensinine and neferine. Our previous
report demonstrated that liensinine and isoliensinine
decreased locomotor activity over 30 min but did notincrease general activity.[11] Therefore, it is unlikely thatliensinine and isoliensinine elicit anti-immobility effects byenhancing locomotor activity. Although some antidepres4

sants like imipramine or maproltiline show antiimmobility effects, they also reduce locomotor activity
similar to liensinine and isoliensinine.[8] It suggests that
sedation and antidepressant effects may be caused throughdifferent mechanisms.
The serotonergic and noradrenergic system has been
implicated in the mechanism of action of several antidepressants.[21] Selective serotonin reuptake inhibitors inhibit
5-HT transporter proteins and reuptake of 5-HT, which
elevates 5-HT levels in the synaptic cleft.[21,22] Mirtazapine
inhibits the hetero α2 receptor on serotonergic neurons tofacilitate 5-HT release.[23] We found that the selective serotonin reuptake inhibitors fluvoxamine or paroxetine elicit
antidepressant-like effects in mice and that these effects are
mediated by 5-HT1A receptors.[24,25] It has been reported thatmirtazapine stimulates 5-HT1A receptors, which contributes© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

Yumi Sugimoto et al.

Bisbenzylisoquinoline against depression

200
150

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***

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50
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5
1
Prazosin (mg/kg)

Immobility time (s)Immobility time (s)250SalineIsoliensinine

300
250
200
150

***

***

***

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50
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5
Prazosin (mg/kg)

SalineNeferine

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Immobility time (s)SalineLiensinine

300

250
200
150

***

***

***

100
50
0

0
1
5
Prazosin (mg/kg)

Figure 5 Effects of prazosin on bisbenzylisoquinolines-induced anti-immobility in mice. Results are the mean ± SE (n = 5–8). Prazosin was given
30 min before liensinine (50 mg/kg), isoliensinine (50 mg/kg) and neferine (50 mg/kg). ***P < 0.001 vs saline of the respective group. ###P < 0.001
vs saline + respective alkaloid-treated group.

to its antidepressant effects.[23] Our previous report demonstrated that antidepressant-like effects induced by neferine
were antagonized by pretreatment with the 5-HT1A receptor
antagonist.[8] Thus, we examined the involvement of 5-HT1A
receptors in the antidepressant-like effects of liensinine andisoliensinine.
The selective 5-HT1A receptor antagonist WAY 100635
significantly reduced the anti-immobility effects ofliensinine and isoliensinine. These results suggest thatliensinine and isoliensinine elicit antidepressant-like effects
through 5-HT1A receptors.
Evidence of the involvement of 5-HT1A receptors in theantidepressant-like effects of several drugs has been accumulated.[22,26,27] Selective 5-HT1A receptor agonists suchas 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)
and gepirone elicit anti-immobility effects in mice andrats.[8,26,28] These agonists stimulate the 5-HT1A receptor
directly and induce antidepressant-like effects. We formerly
demonstrated that 8-OH-DPAT elicits anti-immobility
effects in mice and its effects were antagonized by the
5-HT1A receptor antagonist WAY 100635.[8] The present
study further supports the importance of 5-HT1A receptors
in the antidepressant-like effects in the FST.
Bisbenzylisoquinoline alkaloids cause antidepressant-like
effects via the 5-HT1A receptor. However, it is not clear
whether they cause antidepressant-like effects as direct
5-HT1A receptor agonists. Therefore, we examined the influence of PCPA on the antidepressant-like effects ofliensinine, isoliensinine and neferine to assess their association with serotonergic neurons.
PCPA inhibits 5-HT synthesis and decreases brain levelsof 5-HT.[29] PCPA attenuated the antidepressant-like effects
of liensinine, isoliensinine and neferine. Although PCPA
decreases brain 5-HT contents, PCPA itself did not alter
immobility time. In previous studies with PCPA, immobility was not significantly changed, but the anti-immobility
effects of drugs affecting serotonergic mechanisms werereduced.[30–32]

The finding with PCPA suggested that bisbenzylisoquinolines were not direct 5-HT1A receptor agonists andthat they modify neurotransmission at presynaptic sites.
Modification of 5-HT neurons may be derived by facilitation of 5-HT release from nerve terminals, inhibition of
5-HT reuptake at 5-HT transporter sites, or inhibition of
breakdown of 5-HT by monoamine oxidase. Studies on
detailed mechanisms on 5-HT neurotransmission are
required.
It has been reported that α1-adrenoceptor is involved indepression. The antidepressant-like effects induced byseveral drugs, including noradrenaline reuptake inhibitors,
are mediated by the α1-adrenoceptor[33–35] because theseeffects are antagonized by α1-adrenoceptor antagonists.
We therefore studied the effects of the α1-adrenoceptor
α-antagonist prazosin on the anti-immobility effects ofbisbenzylisoquinolines. Prazosin did not affect liensinine,isoliensinine and neferine-induced anti-immobility effects.
These results suggest that α1-adrenoceptor is not related toanti-immobility effects of these alkaloids.
Our previous study showed that liensinine, isoliensinineand neferine induce sedation in mice.[11] Previously, wedemonstrated the relationship between the chemical structure and sedative effects of bisbenzylisoquinoline alkaloids
from the seeds of Nelumbo nucifera Gaertner. A hydroxyl
group at C-12 or C-7′ of these alkaloids (Figure 1) may
contribute to their sedative effects.[11] Liensinine andisoliensinine, which have a hydroxyl group at C-12 andC-7′, respectively, produced more potent sedative effects
than neferine.[11] Because liensinine shows antidepressantlike effects at the lower dose, hydroxyl group at C-12 mayenhance central effects of bisbenzylisoquinolines. Previous
studies suggest that bisbenzylisoquinolines elicited sedation
without toxicological signs.[7,11] Although effects of thehigher doses are required to examine, our present findings
suggest that bisbenzylisoquinoline alkaloids from theembryos of the seeds of Nelumbo nucifera Gaertner may be
drug candidates for the treatment of depression.

© 2015 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

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Bisbenzylisoquinoline against depression

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Conclusions

Declaration

We found that the bisbenzylisoquinoline alkaloids liensinine
and isoliensinine-induced antidepressant-like effects inmice. Our results suggest that the antidepressant-like effectsof bisbenzylisoquinoline alkaloids are closely associatedwith serotonergic mechanisms.

Conflict of interest

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