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J Nat Med
DOI 10.1007/s11418-017-1140-3
ORIGINAL PAPER
Piperine‑like alkamides from Piper nigrum induce BDNF
promoter and promote neurite outgrowth in Neuro‑2a cells
Young Sook Yun1 · Sachie Noda1 · Shigeru Takahashi1 · Yuji Takahashi1 ·
Hideshi Inoue1 Received: 4 August 2017 / Accepted: 2 October 2017
© The Japanese Society of Pharmacognosy and Springer Japan KK 2017
Abstract Black pepper (Piper nigrum) contains a variety
of alkamides. Among them, piperine has been reported to
have antidepressant-like effects in chronically stressed mice,
but little is known about the biological activity of other alkamides. In this study, we investigated the effects of alkamides
from white pepper (P. nigrum) on neuronal cells. Twelve
alkamides were isolated from white pepper MeOH extracts,
and their chemical structures were identified by NMR and
MS analyses. The compounds were subjected to assays using
the luciferase-reporter gene under the control of the BDNF
promoter or cAMP response element in mouse neuroblastoma Neuro-2a cells. In both assays, marked reporter-inducing activity was observed for piperine (1), piperettine (2) and
piperylin (7), all of which have in common an (E)-5-(buta1,3-dien-1-yl)benzo[d] [1, 3] dioxole moiety. Piperettine
(2) and piperylin (7) tended to increase endogenous BDNF
protein levels. Furthermore, piperylin (7) promoted retinoic
acid-induced neurite outgrowth. These results suggest that
piperylin (7), or analogues thereof, may have a beneficial
effect on disorders associated with dysregulation of BDNF
expression, such as depression.
Keywords Piper nigrum · Alkamides · BDNF · Neurite
outgrowth
* Young Sook Yun
yun@toyaku.ac.jp
1
Graduate School of Life Sciences, Tokyo University
of Pharmacy and Life Sciences, 1432‑1 Horinouchi,
Hachioji, Tokyo 192‑0392, Japan
Introduction
Pepper (Piper) species are widely distributed in tropical and
subtropical regions and have been used as spice or folk medicine in Latin America and the West Indies [1]. Black pepper
is made from unripe fruit of P. nigrum, while white pepper
is made from the seed of the fully ripe fruit with the outer
layer removed. Piperine, the pungent principle of pepper (P.
nigrum and related species), is formed by a condensation
reaction of N-heterocycle piperidine and thioester piperoylCoA [2], and has diverse pharmacological and biological
properties, including anti-oxidant, anti-inflammatory, and
anti-carcinogenic effects in cultured cells and experimental animals, including rodents [3]. It has also been reported
that piperine treatment improves depression-like symptoms
of chronically mild stressed mice via brain-derived neurotrophic factor (BDNF) signaling [4, 5].
BDNF, a member of the nerve growth factor family of
neurotrophic factors [6], is highly expressed in the hippocampus, striatum and cortex and is implicated in differentiation and survival of neurons in the central nervous
system [7]. Clinical studies have revealed that patients with
major depression have lower serum levels of BDNF, which
can be reversed by antidepressant treatment [8]. BDNF gene
expression is regulated by at least nine promoters [9], among
which promoter IV is the most important in controlling neuronal activity and neuronal activity-dependent expression of
BDNF in vitro and in vivo [10, 11].
It has been reported that the concentration of cAMP
response element-binding protein (CREB) is decreased in
the cortex of patients with depression [12]. On the other
hand, an increase in CREB activity in the rodent hippocampal dentate gyrus by direct injection of CREB-encoding
virus has an antidepressant-like effect in the forced swim test
and the learned helplessness test [13]. CREB is essential for
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upregulation of BDNF transcription, but not for the behavioral or endocrine response to antidepressant drugs [14].
Therefore, increased BDNF expression may contribute to
the therapeutic effects of antidepressants.
Beyond piperine, there are few reports addressing the biological activities of alkamides. In this study, we investigated
the effects of 12 alkamides, including piperine from white
pepper, on BDNF expression in Neuro-2a cells and detected
BDNF-inducing activity for two piperine-like alkamides.
Materials and methods
Plant materials
Malaysian white peppercorns were purchased from Tochimototenkaido Co., Ltd. (Osaka, Japan), and a voucher specimen was deposit in the Laboratory of Molecular and Chemical Biology, School of Life Sciences, Tokyo University of
Pharmacy and Life Sciences (Pn-2010).
Chemicals
J Nat Med
60, 65, and 75% aqueous acetonitrile, respectively, gave the
compounds 3 (53 mg), 4 (65.6 mg), and 9 (4.0 mg), the compounds 5 (37.5 mg) and 11 (10.3 mg), and the compounds
6 (4.3 mg) and 10 (6.0 mg). Fr. A-IV (5 g out of 19.9 g)
was fractioned into seven subfractions (Fr. A-IV-1 ~ 7) by
ODS column chromatography. The evaporated subfraction
Fr. A-IV-3 (200 mg) was separated via preparative HPLC,
which gave compound 7 (11.6 mg) upon elution with 45%
aqueous acetonitrile. In the same way, 150 mg of the evaporated subfraction Fr. A-IV-7 gave compounds 2 (12.3 mg)
and 8 (10.8 mg).
Instrumentation
NMR spectra were measured on Bruker DRX-500 and DPX400 spectrometers (Bruker BioSpin GmbH, Rheinstetten,
Germany) at 300 K. The 1H-NMR chemical shifts in ­CDCl3
were calibrated to the residual resonance at 7.26, and the
13
C-NMR chemical shifts were calibrated to the residual
­CHCl3 peak at 77.0. Mass spectra were obtained using a
Micromass LCT spectrometer (Waters Corporation, Milford,
MA, USA).
Dulbecco’s modified Eagle’s medium (DMEM) powder was
purchased from Nissui Pharmaceutical Co., Ltd. (Tokyo,
Japan). l-Glutamine was purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Forskolin was purchased
from Sigma-Aldrich (St. Louis, MO, USA). All organic
solvents were purchased from Kanto Chemical Co., Inc.
(Tokyo, Japan).
WST‑8 assay
Extraction, isolation and purification of compounds
from white pepper
Cell culture and DNA transfection
White pepper from P. nigrum (1.0 kg) was extracted with
methanol (2 L × 3) at 40 °C. After filtration, the solvent was
evaporated under reduced pressure. The methanolic residue
(99.5 g) was suspended in water and then partitioned successively with n-hexane, ethyl acetate, and n-butanol. The
fractions were dried in vacuo to give n-hexane (14.9 g), ethyl
acetate (51.9 g), n-butanol (2.0 g) extracts and a water-soluble portion. The ethyl acetate extract was loaded onto a
silica gel column and eluted sequentially with hexane/ethyl
acetate mixtures (9:1, 8:2, 6:4, and 1:1, v/v) to give eight
fractions (Frs. A-I to A-VIII). Preparative HPLC was carried out on a Shimadzu LC-6AT system equipped with an
SPD-10AVP detector (Shimadzu Co., Kyoto, Japan) and a
reversed-phase column (Mightysil RP-18 prep [5 µm, 20 ×
250 mm]; Kanto Chemical Co., Inc., Tokyo, Japan), using
aqueous acetonitrile as mobile phase at a flow rate of 5 mL/
min. Upon elution with 55% aqueous acetonitrile, Fr. A-III
(24.6 g) yielded compound 1 (3.2 g), which is a major constituent of this plant. Subsequently, stepwise elution with
13
Cell viability was assessed by the WST-8 assay. WST
conversion was measured using the Cell Counting Kit-8
(Dojindo Molecular Technologies, Kumamoto, Japan)
according to the manufacturer’s instructions. All tests were
carried out in triplicate.
Mouse neuroblastoma Neuro-2a cells were obtained from
the RIKEN BioResource Center (Tsukuba, Japan). The
cells were cultured in DMEM supplemented with 10% fetal
bovine serum and 2 mM glutamine. The cells were incubated
at 37 °C under 5% C
­ O2. DNA transfection was performed
using the FuGENE 6 transfection reagent (Roche Diagnostics, Indianapolis, IN, USA) according to the manufacturer’s
instructions.
Transient transfection and reporter gene assay
To normalize transfection efficiency, pRL-SV40 (Promega, Madison, WI, USA) was used as a co-transfection
control. Neuro-2a cells were transiently co-transfected with
the plasmids pRL-SV40 and pGL4.29[luc2P/CRE/Hygro]
(Promega) or hBDNFpIV (−204/+320)-Luc, kindly gifted
from Dr. Timmusk [21], and allowed to grow to confluence
for 24 h. Then, the cells were seeded in 24-well plates at a
density of 1.0 × 105 cells per well and incubated at 37 °C.
After 24 h, samples (final concentration of 10 µM for the
J Nat Med
isolated compounds) were added to the cells. After incubation at 37 °C for 4 h, the cells were washed with PBS and
lysed with Passive Lysis Buffer (Promega). The luciferase
activity in the cell lysates was determined with the DualLuciferase Assay System (Promega) using the Lumat LB
9501 luminometer (Berthold Technologies, Bad Wildbad,
Germany).
Western blot analysis
Cells were washed and harvested in ice-cold PBS and then
lysed with a lysis buffer (150 mM NaCl, 50 mM Tris–HCl
pH 8.0, 0.5% NP-40 and 0.5 M EDTA) containing cOmplete™ Protease Inhibitor Cocktail (Roche) and 200 mM
phenylmethylsulfonyl fluoride (PMSF; Nacalai Tesque,
Kyoto, Japan). Protein concentration was determined using
a BCA protein assay kit (Thermo Fisher Scientific, Waltham,
MA, USA). The lysates were boiled at 95 °C for 5 min, separated by SDS-PAGE, transferred to polyvinylidene difluoride
transfer membranes, hybridized with primary and secondary
antibodies and visualized using Amersham™ ECL™ Prime
Western Blotting Reagent (GE Healthcare Bio-Sciences, Piscataway, NJ, USA) according to the manufacturer’s instructions. The membranes were incubated with the following
antibodies: anti-BDNF (1:1000; Abcam, Cambridge, UK),
-actin (1:10000; Sigma-Aldrich, St. Louis, MO, USA) and
anti-rabbit HRP-conjugated secondary antibody (1:10000;
Santa Cruz Biotechnology, Dallas, TX, USA) for BDNF, and
anti-mouse HRP-conjugated secondary antibody (1:10000;
Santa Cruz Biotechnology) for -actin.
Measurement of neurite outgrowth
Cells (1 × 103) were seeded on cover slips pre-coated with
poly-l-lysine in a 35-mm dish. For the neurite outgrowth
analysis, cells were observed under a phase-contrast light
microscope (Olympus CKX41) at 100-fold magnification.
Images have been taken at 33-fold magnification, and neurite
was counted using the ImageJ program (National Institutes
of Health, Rockville, MD, USA). Neurites were defined as
processes with a length equivalent to one or more diameters
of the cell body.
Statistical analysis
No data were excluded from analysis. Statcel 3 software was
used to perform one-way analysis of variance (ANOVA)
with Tukey–Kramer or Dunnett’s multiple comparisons
tests on datasets for which statistical significance is indicated (except the protein expression data). All figures of
functional data are presented as the mean ± standard error
of the mean SEM.
Results
Isolation and identification of alkamides from methanol
extracts of white pepper
Methanolic extract from white pepper was dissolved in
water and successively extracted with hexane, ethyl acetate,
and n-butanol. The ethyl acetate fraction that had the largest amount of ingredients was subjected to purification by
­SiO2 column chromatography and HPLC, and 12 compounds were isolated. Spectroscopic analyses, including MS
and NMR, identified the compounds as piperine (1) [15],
piperettine (2) [16], pipernonaline (3) [15], dehydropipernonaline (4) [17], piperrolein B (5) [17], piperchabamide
C (6) [18], piperylin (7) [16], piperamide-C9:3(2E,4E,8E)
(8) [16], retrofractamide-A (9) [16], guineensine (10) [15],
(2E,4E)-N-isobutyldodeca-2,4-dienamide (11) [19], and
(2E,4E,12Z)-N-isobutylocatadeca-2,4,12-trienamide (12)
[15] (Fig. 1). These compounds can be classified into four
types of alkamides, including piperidinyl (1-6), pyrrolidinyl
(7 and 8), and isobutylaminyl amides (9 and 10) of an unsaturated aliphatic acid with a methylenedioxyphenyl moiety,
and N-isobutylaminyl amides of an unsaturated aliphatic
acid without a methylenedioxyphenyl group (11 and 12).
Compound 6 was isolated from P. nigrum for the first time.
Piperine‑like alkamides increase human BDNF‑IV
promoter‑mediated luciferase reporter gene expression
and endogenous BDNF protein expression
The effects of the 12 compounds on BDNF expression were
investigated in the mouse neuroblastoma cell line, Neuro-2a.
Cytotoxicity was evaluated by the WST-8 assay, and most
of the compounds did not markedly affect cell viability at
any concentration (Fig. 2). For the luciferase reporter gene
assay, we used the promoter IV region (−204/+320) of the
human BDNF gene, which is important for neuronal activity-dependent expression of BDNF. [20]. The reporter gene
plasmid was introduced into Neuro-2a cells, and effects of
the compounds on reporter gene expression were examined
at 10 µM. Of the 12 compounds, 1, 2, and 7 significantly
raised the level of reporter gene expression compared with
the vehicle control (P < 0.01) (Fig. 3a). On this basis, we
examined the effects of these compounds on the endogenous
BDNF protein levels. As shown in Fig. 3b, although these
compounds tended to increase endogenous BDNF protein
levels, the increase was not significant.
Piperine‑like alkamides increase CRE‑mediated
luciferase reporter gene expression
The human BDNF-IV gene promoter region (−204/+320)
contains a cAMP response element (CRE) [20], therefore
13
J Nat Med
O
O
O
O
N
N
O
O
(2) Piperattine
(1) Piperine
O
O
O
O
N
O
N
O
(3) Pipernonaline
(4) Dehydropipernonaline
O
O
O
O
N
N
O
O
(5) Piperolein B
(6) Piperchabamide C
O
O
O
O
N
O
N
O
(7) Piperylin
(8) Piperamide-C9:3(2E, 4E, 8E)
O
O
O
O
N
H
O
N
H
O
(10) Guineenisine
(9) Retroftactamide A
O
O
N
H
N
H
(11) (2E, 4E)-N-isobuyldodeca-2, 4-dienamide (12) (2E,4E,12Z)-N-i sobutyloctadeca-2,4,12-trienamideide
Fig. 1 Structures of compounds 1–12 isolated from white pepper
180
50 µM
160
10 µM
cell viability (%)
140
5 µM
120
100
80
60
40
20
0
control
1
2
3
4
5
6
Fig. 2 Influence of compounds 1–12 on Neuro-2a cell viability. Cell
viability was measured by the WST-8 assay after being cultured with
different concentrations of the compounds (1-12) for 24 h. Etopo-
13
7
8
9
10
11
12
etoposide
side (5 µM) was used as positive control. Data are represented as
mean ± SEM of three independent experiments
J Nat Med
B
2.5
2.0
**
**
BDNF
(14kDa)
**
-actin
Relative band density of BDNF/ -actin
1.5
1.0
0.5
0.0
control 1
2
3
4
5
6
7
8
9 10 11 12 FSK
Fig. 3 Influence of compounds 1–12 on BDNF expression in Neuro2a cells. a Influence of the compounds on luciferase reporter induction mediated by the BDNF gene promoter IV in the Neuro-2a cells
transfected with human BDNF-IV promoter (−204/+320)-Luc. Relative fold increase in luciferase activity after treatment with a compound for 4 h compared to the vehicle control (DMSO) is shown.
it is possible that the inducible effects of the alkamides
depend on CREB. To verify whether the alkamides
promote CRE-mediated transcriptional induction, we
examined the effects of the compounds on reporter gene
expression using a plasmid pGL4.29 [luc2P/CRE/Hygro],
in which the luciferase gene was placed under the control
of a CRE. As presented in Fig. 4, compounds 1, 2, and
7 significantly induced CRE-mediated luciferase gene
expression (P < 0.01), as was the case for the reporter
gene assays using the BDNF-IV promoter. Therefore, the
inducible activity of the alkamides may be at least partially mediated by the CRE.
Piperylin (7) promote neurite outgrowth induced
by retinoic acid
It has been reported that intraventricular infused BDNF
increases the number of newly synthesized neurons in the
striatum, thalamus, and hypothalamus of adult rats [21].
Since the piperine-like alkamides raised the endogenous
BDNF protein levels in Neuro-2a cells, we investigated
whether the compounds also promote neuronal differentiation. Kaplan et al. reported that induction of TrkB by retinoic
acid mediated biologic responsiveness to BDNF. [22] Therefore, we compared retinoic acid-induced neurite outgrowth
2.1
1.8
1.5
1.2
0.9
0.6
0.3
0
control
1
2
7
FSK indicated forskolin (10 µM) used as positive control. b Western
blot analysis on endogenous BDNF levels after 5 h of treatment with
compound 1, 2 or 7 (10 µM, respectively). Data normalized with
-actin levels are represented as mean ± SEM of three independent experiments. Statistically significant differences compared to the
vehicle control are marked by asterisks (**P < 0.01)
Relative luciferase induction (fold)
Relative luciferase induction (fold)
A
3.5
3.0
2.5
**
**
**
**
2.0
1.5
1.0
0.5
0.0
control 1
2
3
4
5
6
7
8
9 10 11 12 FSK
Fig. 4 Influence of compounds 1-12 on CRE-mediated luciferase
induction in the Neuro-2a cells transfected with pGL4.29[luc2P/CRE/
Hygro]. Relative fold increase in luciferase activity after treatment
with compounds (10 µM) for 4 h compared to the vehicle control
(DMSO) is shown. FSK indicated forskolin (0.1 µM) used as positive control. Data are represented as mean ± SEM of three independent experiments. Statistically significant differences compared to the
vehicle control are marked by asterisks (**P < 0.01)
of Neuro-2a cells treated with compounds 1, 2 or 7 and nontreated cells. As shown in Fig. 5, compound 7 significantly
promoted neurite outgrowth (P < 0.05).
13
J Nat Med
A
control
1
2
7
B
300
*
Relative neurites length
250
200
150
100
50
0
control
1
2
7
Fig. 5 Influence of compounds 1, 2, and 7 on neurite outgrowth in
Neuro-2a cells. a Neuro-2a cells were pre-treated for 5 h with 10 µM
compound 1, 2, or 7, and then 20 µM retinoic acid was added. The
cell morphology was observed after 24 h, and morphological images
were captured under a phase contrast microscope. b Relative length
of extended neurites were measured using the ImageJ software program (National Institutes of Health, Rockville, MD, USA). Fifty cells
were randomly chosen for each group, and the length of the longest neurite was measured for each cell. Box boundaries indicate the
upper and lower quartiles, with the median plotted in thick black with
whiskers extending to the most extreme values that are still considered not to be outliers. Statistically significant differences compared
to the vehicle control are marked by asterisks (*P < 0.05)
Discussion
lacking promoter IV-driven BDNF gene expression display
depression-like behavior [25]. In a rodent model of chronic
unpredictable mild stress, piperine treatment reverses the
behavioral changes and the decreased BDNF levels in the
hippocampus and frontal cortex [26]. Consistent with this,
the piperine-like alkamides, piperettine (2) and piperylin
(7), enhanced the BDNF promoter-driven reporter gene
expression (Fig. 3a) and showed a tendency to increase
endogenous BDNF levels in Neuro-2a cells (Fig. 3b).
Several natural products have been reported to raise the
levels of BDNF mRNA or protein, including berberine [27],
3,6′-disinapoyl sucrose [28], rosmarinic acid [29], and curcumin [30]. Among these, the (E)-5-(buta-1,3-dien-1-yl)
benzo[d] [1, 3] dioxole moiety shared by the alkamides piperine (1), piperettine (2) and piperylin (7) is also found in
berberine. Thus, the structure–activity relationship suggests
that the piperine alkamides induce BDNF expression by a
mechanism that is shared with berberine or the sinapic acid
derivatives.
In this study, 12 alkamides were isolated from white pepper,
and of these, piperine (1), piperettine (2) and piperylin (7)
were found to significantly raise reporter gene expression
driven by both the BDNF-IV promoter and CRE. Although
some of the other compounds also significantly induced
expression, none showed induction activity as marked as
that exhibited by these three compounds. In terms of the
relationship between structure and activity, the compounds
with the most prominent activity have an (E)-5-(buta-1,3dien-1-yl)benzo[d] [1, 3] dioxole moiety in common, while
the others do not.
Depressed patients have reduced serum BDNF levels,
and antidepressant treatment restores BDNF expression
to control levels [15]. Cerebral post-mortem samples
from the brains of depressed patients reveal a reduction
in BDNF levels [23], and antidepressants increase BDNF
mRNA expression in the brain [24]. In addition, mice
13
J Nat Med
BDNF expression is regulated by multiple pathways,
including CREB signaling, which regulates gene expression
networks that promote synaptic and neural plasticity and
is involved in depression and antidepressant-like responses
[31]. Because there is a CRE in the BDNF-IV promoter
and because piperine (1), piperettine (2) and piperylin (7)
induced reporter gene expression under the control of the
CRE, the inducing activity of these alkamides may be mediated by CREB. However, 10 µM forskolin, a representative
activator for adenylate cyclase, did not raise the reporter
gene expression driven by the BDNF-IV promoter as markedly as these three alkamides, while 0.1 µM forskolin and
the alkamides comparably induced CRE-driven reporter
gene expression in Neuro-2a cells. These results suggest
that the alkamides induce BDNF-IV promoter-driven gene
expression in a manner that may be different from forskolin.
6.
7.
8.
9.
10.
11.
Conclusion
12.
In this study, piperine-like alkamides induced BDNF-IV
promoter in Neuro-2a cells, and piperylin (7) significantly
promoted retinoic acid-induced neurite outgrowth. We identified a structure–activity relationship among the alkamides
and other compounds that show BDNF-inducing activity.
Therefore, piperine-like alkamides, or other compounds with
a similar structure, may be useful therapeutic agents for the
treatment of depression.
13.
14.
15.
Acknowledgements This work was supported in part by the Platform for Drug Discovery, Informatics, and Structural Life Science from
the Ministry of Education, Culture, Sports, Science and Technology
(MEXT), Japan, and by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities.
16.
Compliance with ethical standards 17.
Conflict of interest The authors declare that they have no conflict
of interest.
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