European Journal of Pharmacology 853 (2019) 129–135

Contents lists available at ScienceDirect

European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Neuropharmacology and analgesia

Sertraline inhibits nerve growth factor-induced neurite outgrowth in PC12 T

cells via a mechanism involving the sigma-1 receptor
⁎
Yukari Matsushimaa,b, Kazuki Teradac, Chiaki Kameia, Yumi Sugimotod,
a
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Yasuda Women's University, 6-13-1 Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan
b
Department of Kampo and Natural Product Chemistry, Yokohama University of Pharmacy, 601 Matanocho, Totsuka-ku, Yokohama 245-0066, Japan
c
Laboratory of Drug Design and Drug Delivery, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
d
Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiohno, Himeji 670-8524, Japan

A R T I C LE I N FO A B S T R A C T

Keywords: The selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and sertraline show a high affinity for sigma-1
Nerve growth factor receptors. Fluvoxamine enhances nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells via a
Neurite outgrowth sigma-1 receptor-mediated mechanism, which suggests that neurogenesis may be involved in the antidepressant
Sertraline action of fluvoxamine. However, the effects of sertraline on neurite outgrowth remain unclear. Here, we report
Selective serotonin reuptake inhibitor
the effects of sertraline on NGF-induced neurite outgrowth in PC12 cells. At concentrations above 0.3 μM, ser-
Sigma-1 receptor
PC12 cells
traline inhibited neurite outgrowth induced by NGF (50 ng/mL) in PC12 cells in a concentration-dependent
manner. At 0.3–3 μM, sertraline inhibited NGF-induced neurite outgrowth; however, had no effect on cell via-
bility. This suggests that at these concentrations, sertraline inhibits NGF-induced neurite outgrowth without
causing cell toxicity. Because sertraline has a high affinity for the sigma-1 receptor, we investigated whether this
receptor is involved in sertraline's inhibitory effect on NGF-induced neurite outgrowth. The effect was reversed
by both the sigma-1 receptor agonist PRE-084 and the sigma-1 receptor antagonist NE-100. These results suggest
that sertraline inhibits NGF-induced neurite outgrowth in PC12 cells by acting as an inverse agonist of the sigma-
1 receptor in this system.

1. Introduction intracellular endoplasmic reticulum membranes. It is involved in the

Various pathways are implicated in the pathology of depression,
including the neurotransmission of serotonin (5-hydroxytryptamine, 5-
HT), noradrenaline, or glucocorticoid secretion (Libraries, 2001; Liu
et al., 2006; Nestler et al., 2002; Ressler and Nemeroff, 2000). Selective
serotonin reuptake inhibitors (SSRIs) are widely used for the treatment
of depression. SSRIs inhibit the 5-HT transporter, leading to an eleva-
tion of 5-HT levels in the synaptic cleft (Hyttel, 1994; Sangkuhl et al.,
2009; Zhou et al., 2009). Although increases in 5-HT levels are elicited
rapidly, a few weeks of treatment with SSRIs are required before an
improvement in symptoms (Berton and Nestler, 2006; Wong and
Licinio, 2001). Therefore, mechanisms other than 5-HT levels may be
related to the antidepressant effects of SSRIs.
Sigma receptors were discovered in 1976 and are classified as
sigma-1 and sigma-2 receptors (Hellewell and Bowen, 1990). The
sigma-1 receptor is widely distributed in several tissues. In the central
nervous system, it is highly expressed in the hippocampus, frontal
cortex, and hypothalamus (Collina et al., 2013), specifically on
regulation of mitochondrial calcium concentration and reduction of
endoplasmic reticulum stress (Hayashi et al., 2000; Hayashi and Su,
2007). The sigma-1 receptor has been suggested to play an important
role in psychiatric disorders, and there is increasing interest in the re-
lationship between this receptor and depression (Albayrak and
Hashimoto, 2017; Furuse and Hashimoto, 2009; Hindmarch and
Hashimoto, 2010; Ishikawa and Hashimoto, 2010). It has been reported
that sigma-1 receptor knockout mice exhibit depression-like behavior
(Chevallier et al., 2011). Sigma-1 receptor agonists such as SA4503 and
UMB23 have antidepressant effects in the forced-swim and tail sus-
pension tests in mice, which are used to evaluate antidepressants
(Banister and Kassiou, 2012; Fukunaga and Moriguchi, 2017; Skuza and
Rogó, 2007; Sugimoto et al., 2012; Wang et al., 2007). In addition,
sigma-1 receptor agonists enhanced neuroplasticity, which may also be
involved in the action of antidepressants (Hayashi and Su, 2004;
Kimura et al., 2013; Takebayashi et al., 2002).
The SSRI fluvoxamine has a strong affinity for the sigma-1 receptor
(Narita et al., 1996) and enhances nerve growth factor (NGF)-induced

⁎
Corresponding author.
E-mail address: yumisugi@gm.himeji-du.ac.jp (Y. Sugimoto).

https://doi.org/10.1016/j.ejphar.2019.03.032
Received 25 December 2018; Accepted 18 March 2019
Available online 19 March 2019
0014-2999/ © 2019 Elsevier B.V. All rights reserved.
Y. Matsushima, et al.
Fig. 1. Effects of SSRIs on neurite outgrowth in the presence and absence of NGF (50 ng/mL). (A) NGF + fluvoxamine. (B) NGF + sertraline. (C) NGF + paroxetine.
(D) Fluvoxamine alone. (E) Sertraline alone. (F) Paroxetine alone. Values represent means ± S.E.M (n = 6). * * P < 0.01 vs. NGF.
neurite outgrowth in PC12 cells through stimulation of the sigma-1
receptor; its effects are blocked by sigma-1 receptor antagonism (Ishima
et al., 2014; Nishimura et al., 2008). This suggests that the sigma-1
receptor has a role in neuroplasticity, and may be connected to the
antidepressant effects of fluvoxamine. Another SSRI, sertraline, also has
an affinity for the sigma-1 receptor. It was previously reported that
sertraline inhibits NGF-induced neurite outgrowth in PC12 cells, in
contrast to fluvoxamine (Ishima et al., 2014). However, whether the
sigma-1 receptor is involved in this effect remains unknown. To address
this, we investigated the inhibitory effect of sertraline on NGF-induced
neurite outgrowth in PC12 cells compared to fluvoxamine, and the
involvement of the sigma-1 receptor in this effect.
2. Material and methods
2.1. Reagents
2.5S-NGF from mouse submaxillary glands (mNGF 2.5S) was pur-
chased from Alomone Labs (Jerusalem, Israel). Sertraline hydro-
chloride, fluvoxamine hydrochloride and paroxetine hydrochloride
were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo,
Japan). PRE-084 hydrochloride and NE-100 hydrochloride were pur-
chased from Santa Cruz Biotechnology, Inc. (CA, USA).
130
European Journal of Pharmacology 853 (2019) 129–135
2.2. Cell culture
PC12 cells (RIKEN Cell Bank, Tsukuba, Japan) were cultured at
37 °C and 5% CO2, in Dulbecco's modified Eagle's medium (DMEM)
(Gibco-Life Technologies, Gaithersburg, MD, USA) supplemented with
nutrient mixture F-12 (Gibco-Life Technologies), 10% (v/v) fetal bovine
serum (FBS) (Gibco-Life Technologies) and 1% (v/v) penicillin/strep-
tomycin (Nacalai Tesque, Kyoto, Japan). To measure neurite sprouting,
PC12 cells were plated at a density of 1.0 × 105 cells/dish on type 1
collagen-coated, 60-mm tissue culture dishes in DMEM/F12 containing
10% FBS with 1% penicillin/streptomycin and cultured for 24 h.
2.3. Drug treatment and measurement of neurite outgrowth
Fluvoxamine, sertraline and paroxetine were dissolved in ethanol
and final volume of ethanol was no more than 0.1%. PRE-084 and NGF
were dissolved in distilled water which final volume was no more than
0.1%. Drugs were added to PC12 cells in DMEM/F12 containing 5%
FBS for 24 h. Measurement of neurite outgrowth was evaluated with
modifying previously described (Terada et al., 2014). After 24 h of
treatment, images of 5 randomly selected fields, each containing 10–15
cells, were captured using an inverted phase-contrast microscope
(Nikon, Tokyo, Japan) equipped with a digital camera (Digital Sight DS-
L2 system; Nikon), and 10 cells in each images were measured using
ImageJ version 1.48 v (National Institutes of Health, Bethesda, MD,
USA). Measurement was performed in blinded manner. The neurite
Y. Matsushima, et al.
length is defined as the distance along a neurite, i.e., the distance from
the soma to the end of neurite. The total neirute length of 10 cells for
each treatment condition was calculated to evaluate the neurite out-
growth (Terada et al., 2014).
2.4. Cell viability
Cell viability assay was determined using a the [3-(4,5-di-
methylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay (MTT;
Nacalai tesque, Kyoto, Japan), following the method modifying de-
scribed(Lombardi et al., 2017; Ogra et al., 2016). Cell viability was also
determined using a commercially available kit, CellTiter-Glo Lumines-
cent Cell Viability Assay (Promega KK, Tokyo, Japan) with small
modification (Setoguchi et al., 2018). Both assays were conducted
under the same conditions. Briefly, PC12 cells were seeded at a density
of 1.0 × 104 cells /well. After 24 h, cells were treated with different
concentrations of each drug to another 24 h, and the cell viability was
measured using each reagent. Results are expressed as a percentage of
the absorbance of vehicle-treated culture wells.
2.5. Statistical analysis
All numerical data are presented as the mean ± S.E.M. Statistical
analysis was performed using an analysis of variance followed by
Tukey's post-hoc or Dunnett's tests.
3. Results
3.1. Effects of SSRIs on NGF-induced neurite outgrowth
NGF (50 ng/mL)-induced neurite outgrowth was enhanced by flu-
voxamine (F(4, 25) = 48.56, P < 0.001) (Fig. 1A), and inhibited by
sertraline (F(5, 30) = 572.64, P < 0.001) (Fig. 1B), in a concentration-
dependent manner. Paroxetine did not affect NGF-neurite outgrowth (F
(4, 25) = 0.17, P > 0.05) (Fig. 1C). In addition, none of the drugs
changed neurite outgrowth in the absence of NGF (Fluvoxamine; F(4,
25) = 1.38, P > 0.05, Sertraline; F(5, 30) = 0.87, P > 0.05, Parox-
etine; F(4, 25) = 2.57, P > 0.05) (Fig. 1D–F).
Typical Representative image of phase-contrast photomicrographs
are shown in Fig. 2A-D.
3.2. Effects of SSRIs on PC12 cell viability
The viability of PC12 cells was significantly decreased by treatment
with fluvoxamine at concentrations of 100–300 μM (MTT assay; F(8,
36) = 24.80, P < 0.001, CellTiter assay; F(8, 45) = 286.40,
P < 0.001), sertraline at 10–300 μM (MTT assay; F(8, 36) = 132.78,
P < 0.001, CellTiter assay; F(8, 45) = 275.76, P < 0.001), and par-
oxetine at 30–500 μM (MTT assay; F(8, 36) = 60.28, P < 0.001,
CellTiter assay; F(8, 45) = 916.27, P < 0.001) (Fig. 3).
3.3. Effect of sigma-1 receptor stimulation on NGF-induced neurite
outgrowth in PC12 cells
The sigma-1 receptor agonist PRE-084 (0.01–10 μM) enhanced
neurite outgrowth caused by NGF in a concentration-dependent manner
(F(4, 25) = 73.56, P < 0.001) (Fig. 4A). The potentiating effect of
PRE-084 (1 μM) on NGF-induced neurite outgrowth was blocked by the
sigma-1 receptor antagonist NE-100 (1 μM) (F(3, 20) = 224.04,
P < 0.001) (Fig. 4B).
3.4. Involvement of the sigma-1 receptor in the effects of fluvoxamine and
sertraline in NGF-induced neurite outgrowth
The enhancing effect of fluvoxamine (1 μM) on NGF-induced neurite
outgrowth was blocked by the sigma-1 receptor antagonist NE-100
131
European Journal of Pharmacology 853 (2019) 129–135
(1 μM) (F(3, 20) = 108.41, P < 0.001) (Fig. 5). The inhibitory effect of
sertraline (1 μM) on NGF-induced neurite outgrowth was significantly
reduced by the sigma-1 receptor agonist PRE-084 (0.1 μM) (F(3, 20)
= 35.81, P < 0.001) (Fig. 6A). Furthermore, the inhibitory effect of
sertraline on NGF-induced neurite outgrowth was also reversed by co-
treatment with the sigma-1 receptor antagonist NE-100 (1 μM) (F(3,
20) = 55.43, P < 0.001) (Fig. 6B).
4. Discussion
In this study, we found that sertraline inhibited the NGF-induced
neurite outgrowth without affecting their viability. The effect of ser-
traline was completely blocked by the sigma-1 receptor antagonist.
These findings are the first report that sertraline inhibited the NGF-
induced neurite outgrowth by via the sigma-1 receptor. Some anti-
depressants classified as SSRIs show a high affinity for the sigma-1 re-
ceptor (Ishima et al., 2014; Narita et al., 1996), including fluvoxamine,
which has the highest affinity of these (Ki = 36 nM), and sertraline (Ki
= 57 nM) (Narita et al., 1996). In contrast, the potent SSRI paroxetine
has a low affinity with the sigma-1 receptor (Ki = 1893 nM) (Narita
et al., 1996). Fluvoxamine is a typical antidepressant and is used for
treating depression, obsessive compulsive disorder, and anxiety
(Carrasco and Sandner, 2005). Fluvoxamine enhances NGF-induced
neurite outgrowth in PC12 cells, and this effect is mediated by the
sigma-1 receptor (Nishimura et al., 2008). This observation indicates
that the sigma-1 receptor may be involved in fluvoxamine's mechanism
of action, as it is important in neuronal plasticity and neuropsychiatric
disease (Hashimoto, 2009; Niitsu et al., 2012). Sertraline, another SSRI
with a high affinity for the sigma-1 receptor, inhibits NGF-induced
neurite outgrowth in PC12 cells (Ishima et al., 2014). However, it was
not clear whether these inhibitory effects of sertraline are mediated by
the sigma-1 receptor. Therefore, we examined the involvement of the
sigma-1 receptor in the inhibitory effects of sertraline on NGF-induced
neurite outgrowth in PC12 cells compared with fluvoxamine and par-
oxetine, using a sigma-1 receptor agonist and antagonist.
Fluvoxamine significantly enhanced NGF-induced neurite out-
growth in PC12 cells at concentrations above 0.1 μM, consistent with
results reported by Nishimura et al. (2008). Fluvoxamine had no affect
neurite outgrowth in PC12 cells in the absence of NGF. These results
suggest that fluvoxamine does not act as an NGF-like agonist but en-
hances the stimulation induced by NGF. Sertraline, which has a high
affinity for the sigma-1 receptor, significantly inhibited NGF-induced
neurite outgrowth at concentrations over 0.3 μM, but did not affect
neurite outgrowth in the absence of NGF. Ishima et al. (2014) reported
that sertraline did not inhibit NGF (2.5 ng/mL)-induced neurite out-
growth at 1 μM and had a significant inhibitory effect at 10 μM (Ishima
et al., 2014). This discrepancy in sertraline concentrations that inhibit
neurite outgrowth may be due to differences in experimental condi-
tions, such as NGF concentration (2.5 vs. 50 ng/mL) or duration in
culture (5 days vs. 24 h). We examined neurite outgrowth after 2.5 ng/
mL NGF for 5 days which is the same condition as Ishima et al. (2014).
We confirmed that its neurite outgrowth was similar to 50 ng/mL NGF
for 24 h culture in our present experiments (data is not shown).
Therefore, our experimental condition of 50 ng/mL NGF for 24 h is
sufficient time and NGF concentration. Paroxetine, which has a low
affinity for the sigma-1 receptor, had no effects on PC12 cell neurite
outgrowth in the presence or absence of NGF.
SSRIs show cytotoxicity in several cell lines (Levkovitz et al., 2005;
Nordenberg et al., 1999). In addition, sertraline has been suggested to
show cytotoxicity at lower concentrations than other SSRIs (Kuwahara
et al., 2015). For example, the IC50 value of sertraline for reducing cell
viability in HT29 cells is 14.7 μM, and potency is sertraline >
paroxetine > clomipramine > fluoxetine (Irit et al., 2008). The IC50
value of anticancer effects on HepG2 cells induced by sertraline is
1.24 ± 0.0551 μM, which is 25 times lower than that of fluvoxamine
(Kuwahara et al., 2015). The concentrations of sertraline that
Y. Matsushima, et al. European Journal of Pharmacology 853 (2019) 129–135

Fig. 2. Representative image of phase-contrast photomicrographs. (A) NGF (50 ng/mL) only. (B) NGF + fluvoxamine (1 μM). (C) NGF + sertraline (1 μM). (D)
NGF + paroxetine (1 μM). Scale bars: 50 µm.

significantly inhibit NGF-induced neurite outgrowth are in the same
range as those eliciting cytotoxic effects in other cell lines. Therefore,
there is a possibility that the inhibitory effects of sertraline on NGF-
induced neurite outgrowth may be caused by cytotoxic effects on PC12
cells. However, the cytotoxic effects of SSRI on PC12 cells are not yet
clear. Therefore, we examined their effects on PC12 cell viability.
Fluvoxamine above 100 μM, sertraline above 10 μM and paroxetine
above 30 μM significantly decreased the viability of PC12 cells.
Sertraline had significant inhibitory effects on NGF-induced neurite
outgrowth above concentrations of 0.3 μM, which are lower than those
decreasing cell viability in PC12 cells. These results indicate that at
lower concentrations, sertraline inhibits NGF-induced neurite out-
growth in PC12 cells without affecting their viability. The inhibitory
effects on NGF-induced neurite outgrowth over sertraline 10 μM may be

Fig. 3. Effects of SSRIs on PC12 cell viability. Cell viability is expressed as a percentage of control. (A) Fluvoxamine. (B) Sertraline. (C) Paroxetine. Data represent
means ± S.E.M (n = 9). *P < 0.05, **P < 0.01 vs. control (without SSRI), MTT assay. # P < 0.05, ##P < 0.01 vs. control (without SSRI), CellTiter assay.

132
Y. Matsushima, et al.
Fig. 5. NE-100 blocks fluvoxamine potentiation of NGF-induced neurite out-
growth. PC12 cells were treated with NGF (50 ng/mL), fluvoxamine (1 μM) and
NE-100 (1 μM). Values represent means ± S.E.M (n = 6). **P < 0.01 vs.
NGF + fluvoxamine.
133
European Journal of Pharmacology 853 (2019) 129–135
Fig. 4. Involvement of the sigma-1 receptor in
NGF-induced neurite outgrowth in PC12 cells.
(A) Concentration-dependent effects of the
sigma-1 receptor agonist PRE-084 on neurite
outgrowth induced by NGF (50 ng/mL).
**P < 0.01 vs. NGF. (B) Effect of the sigma-1
receptor antagonist NE-100 (1 μM) on PRE-084
(1 μM)-induced potentiation of neurite out-
growth elicited by NGF (50 ng/mL). Values
represent means ± S.E.M (n = 6).
**P < 0.01 vs. (A) NGF, (B) NGF + PRE-084.
caused, in part, by cytotoxicity.
The sigma-1 receptor may be involved in fluvoxamine's enhance-
ment of NGF-induced neurite outgrowth (Nishimura et al., 2008). We
demonstrated that the selective sigma-1 receptor agonist PRE-084 po-
tentiated NGF-induced neurite outgrowth in a concentration-dependent
manner. Although Rossi et al. (2011) also reported that PRE-084 en-
hances NGF-induced neurite outgrowth in PC12 cells (Rossi et al.,
2011), no reported studies have examined the effects of sigma-1 re-
ceptor antagonism on the action of PRE-084. In the present study, we
have demonstrated that the potentiating effects of PRE-084 were
blocked by co-administration of the sigma-1 receptor antagonist NE-
100. These results indicate that PRE-084 elicits the effect via stimula-
tion of the sigma-1 receptor. The potentiating effects of fluvoxamine on
NGF-induced neurite outgrowth were also significantly blocked by NE-
100, confirming that the augmentation of NGF-induced neurite out-
growth by fluvoxamine is caused by sigma-1 receptor stimulation; in
other words, fluvoxamine acts as a sigma-1 receptor agonist. In con-
trast, sertraline inhibits NGF-induced neurite outgrowth. The involve-
ment of the sigma-1 receptor in the effects of sertraline was not in-
vestigated, but as sertraline has an affinity with the sigma-1 receptor,
Fig. 6. Effects of PRE-084 and NE-100 on NGF-
induced neurite outgrowth inhibition by ser-
traline. PC12 cells were treated with NGF
(50 ng/mL) with or without sertraline (1 μM),
PRE-084 (0.1 μM) or NE-100 (1 μM). (A)
Sertraline + PRE-084. (B) Sertraline + NE-
100. Values represent means ± S.E.M (n = 6).
**P < 0.01 vs. NGF + sertraline.
Y. Matsushima, et al.
we assume it acts as a sigma-1 receptor antagonist/inverse agonist.
Therefore, We examined the effects of the sigma-1 receptor agonist
PRE-084 on NGF-induced neurite outgrowth inhibition by sertraline. At
a low concentration not affecting neurite outgrowth by itself, PRE-084
reversed the effects of sertraline. In addition, the sigma-1 receptor an-
tagonist NE-100 blocked NGF-induced neurite outgrowth inhibition by
sertraline. These results suggesting that the inhibitory effects of ser-
traline on NGF-induced neurite outgrowth are elicited via mechanisms
involving the sigma-1 receptor. Both the sigma-1 receptor agonist and
antagonist in the present study blocked the inhibitory effects of ser-
traline on NGF-induced neurite outgrowth. This suggests that sertraline
behaves as an inverse agonist at the sigma-1 receptor in NGF-induced
neurite outgrowth in PC12 cells, resulting in the inhibition of this
process.
We demonstrated that sertraline inhibited NGF-induced neurite
outgrowth via inhibition of sigma-1 receptor, in contrast to the effects
of fluvoxamine. It was previously reported that the sigma-1 receptor
may be implicated in the efficacy of fluvoxamine on psychotic de-
pression in humans (Furuse and Hashimoto, 2009; Hindmarch and
Hashimoto, 2010). Interestingly, Kishimoto et al. (2010) reported that
in a patient with psychotic major depression, fluvoxamine and sertra-
line had opposite effects (Kishimoto et al., 2010). These findings reveal
the possibility that combining the antidepressants fluvoxamine and
sertraline counteracts sigma-1 receptor-mediated responses. Sigma-1
receptor antagonists improve cognitive impairment in phencyclidine-
treated animals used as a model of schizophrenia (Okuyama et al.,
1995; Okuyama and Nakazato, 1996). It was postulated that in clinical
use, addition of sertraline to antipsychotics may be effective for positive
and negative symptoms in schizophrenia (Thakore et al., 1996). It has
recently been suggested that the sigma-1 receptor antagonist may be
useful as an analgesic (Almansa and Vela, 2014). As sertraline can in-
hibit sigma-1 receptor-mediated responses, it may be useful as a
treatment for schizophrenia or pain.
In summary, we have shown that sertraline inhibits NGF-induced
neurite outgrowth in PC12 cells in a mechanism involving the sigma-1
receptor, and that sertraline acts as an inverse agonist of the sigma-1
receptor in this model. The sigma-1 receptor is speculated to be im-
portant for neural plasticity (Cobos et al., 2008; Hayashi and Su, 2004;
Ishikawa and Hashimoto, 2010; Walker et al., 1990). Therefore, ser-
traline may diminish the pharmacological effects of sigma-1 receptor
agonists (for example fluvoxamine in neuroplasticity). Further studies
are required to clarify the detailed intracellular mechanisms of ser-
traline's action on NGF-induced neurite outgrowth mediated by the
sigma-1 receptor.
Acknowledgements
We acknowledge, with thanks, the assistance of Mr. Takayuki
Watanabe. We thank Julia Slone-Murphy, Ph.D., ELS, from Edanz
Group (www.edanzediting.com/ac) for editing a draft of this manu-
script.
Declaration of interest
None.
References
Albayrak, Y., Hashimoto, K., 2017. Sigma-1 receptor agonists and their clinical implica-
tions in neuropsychiatric disorders. Adv. Exp. Med. Biol. 964, 153–161.
Almansa, C., Vela, J.M., 2014. Selective sigma-1 receptor antagonists for the treatment of
pain. Future Med. Chem. 6, 1179–1199.
Banister, S.D., Kassiou, M., 2012. The therapeutic potential of sigma (σ) receptors for the
treatment of central nervous system diseases: evaluation of the evidence. Curr.
Pharm. Des. 884–901.
Berton, O., Nestler, E.J., 2006. New approaches to antidepressant drug discovery: beyond
monoamines. Nat. Rev. Neurosci. 7, 137–151.
Carrasco, J.L., Sandner, C., 2005. Clinical effects of pharmacological variations in
134
European Journal of Pharmacology 853 (2019) 129–135
selective serotonin reuptake inhibitors: an overview. Int. J. Clin. Pract. 59,
1428–1434.
Chevallier, N., Keller, E., Maurice, T., 2011. Behavioural phenotyping of knockout mice
for the sigma-1 (σ1) chaperone protein revealed gender-related anxiety, depressive-
like and memory alterations. J. Psychopharmacol. 25, 960–975.
Cobos, E.J., Entrena, J.M., Nieto, F.R., Cendán, C.M., Del Pozo, E., 2008. Pharmacology
and therapeutic potential of sigma(1) receptor ligands. Curr. Neuropharmacol. 6,
344–366.
Collina, S., Gaggeri, R., Marra, A., Bassi, A., Negrinotti, S., Negri, F., Rossi, D., 2013.
Sigma receptor modulators: a patent review. Expert Opin. Ther. Pat. 23, 597–613.
Fukunaga, K., Moriguchi, S., 2017. Stimulation of the sigma-1 receptor and the effects on
neurogenesis and depressive behaviors in mice. Adv. Exp. Med. Biol. 964, 201–211.
Furuse, T., Hashimoto, K., 2009. Fluvoxamine monotherapy for psychotic depression: the
potential role of sigma-1 receptors. Ann. Gen. Psychiatry 8, 6–8.
Hashimoto, K., 2009. Sigma-1 receptors and selective serotonin reuptake inhibitors:
clinical implications of their relationship. Cent. Nerv. Syst. Agents Med. Chem. 9,
197–204.
Hayashi, T., Maurice, T., Su, T.-P., 2000. Ca2+ signaling via σ1-receptors: novel reg-
ulatory mechanism affecting intracellular Ca2+ concentration. J. Pharmacol. Exp.
Ther. 293, 788–798.
Hayashi, T., Su, T.-P., 2004. Sigma-1 receptor ligands: potential in the treatment of
neuropsychiatric disorders. CNS Drugs 18, 269–284.
Hayashi, T., Su, T.P., 2007. Sigma-1 receptor chaperones at the ER- mitochondrion in-
terface regulate Ca2+ signaling and cell survival. Cell 131, 596–610.
Hellewell, S.B., Bowen, W.D., 1990. A sigma-like binding site in rat pheochromocytoma
(PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight
suggest a different sigma receptor form from that of guinea pig brain. Brain Res. 527,
244–253.
Hindmarch, I., Hashimoto, K., 2010. Cognition and depression: the effects of fluvoxamine,
a sigma-1 receptor agonist, reconsidered. Hum. Psychopharmacol. 25, 193–200.
Hyttel, J., 1994. Pharmacological characterization of selective serotonin reuptake in-
hibitors (SSRIs). Int Clin. Psychopharmacol. 1, 19–26.
Irit, G.-A., Amichai, Z., Liat, L., Michal, T., Meital, B., Drorit, L., Edward, R., Abraham, W.,
2008. Evaluation of the potential anti-cancer activity of the antidepressant sertraline
in human colon cancer cell lines and in colorectal cancer-xenografted mice. Int. J.
Oncol. 2, 277–286.
Ishikawa, M., Hashimoto, K., 2010. The role of sigma-1 receptors in the pathophysiology
of neuropsychiatric diseases. J. Recept. Ligand Channel Res. 3, 25–36.
Ishima, T., Fujita, Y., Hashimoto, K., 2014. Interaction of new antidepressants with sigma-
1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur.
J. Pharmacol. 727, 167–173.
Kimura, Y., Fujita, Y., Shibata, K., Mori, M., Yamashita, T., 2013. Sigma-1 receptor en-
hances neurite elongation of cerebellar granule neurons via TrkB signaling. PLoS One
8, e75760.
Kishimoto, A., Todani, A., Miura, J., Kitagaki, T., Hashimoto, K., 2010. The opposite
effects of fluvoxamine and sertraline in the treatment of psychotic major depression:
a case report. Ann. Gen. Psychiatry 9, 23.
Kuwahara, J., Yamada, T., Egashira, N., Ueda, M., Zukeyama, N., 2015. Comparison of
the anti-tumor effects of selective erotonin reuptake inhibitors as well as erotonin and
norepinephrine reuptake inhibitors in human hepatocellular arcinoma cells. Biol.
Pharm. Bull. 38, 1410–1414.
Levkovitz, Y., Gil-Ad, I., Zeldich, E., Dayag, M., Weizman, A., 2005. Differential induction
of apoptosis by antidepressants in glioma and neuroblastoma cell lines: evidence for
p-c-Jun, ytochrome c, and caspase-3 involvement. J. Mol. Neurosci. 27, 029–042.
Libraries, G., 2001. Cell. Neurobiol. Depress. 7, 541–547.
Liu, H.H., Payne, H.R., Wang, B., Brady, S.T., 2006. Gender differences in response of
hippocampus to chronic glucocorticoid stress: role of glutamate receptors. J.
Neurosci. Res. 83, 775–786.
Lombardi, A., Trimarco, B., Iaccarino, G., Santulli, G., 2017. Impaired mitochondrial
calcium uptake caused by tacrolimus underlies beta-cell failure. Cell Commun.
Signal. 15, 1–7.
Narita, N., Hashimoto, K., Tomitaka, S., Minabe, Y., 1996. Interactions of selective ser-
otonin reuptake inhibitors with subtypes of sigma receptors in rat brain. Eur. J.
Pharmacol. 307, 117–119.
Nestler, E.J., Barrot, M., DiLeone, R.J., Eisch, A.J., Gold, S.J., Monteggia, L.M., 2002.
Neurobiology of depression. Neuron 34, 13–25.
Niitsu, T., Iyo, M., Hashimoto, K., 2012. Sigma-1 receptor gonists as therapeutic drugs for
cognitive mpairment in neuropsychiatric diseases. Curr. Pharm. Des. 18, 875–883.
Nishimura, T., Ishima, T., Iyo, M., Hashimoto, K., 2008. Potentiation of nerve growth
factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 re-
ceptors and cellular signaling pathways. PLoS One 3, e2558.
Nordenberg, J., Fenig, E., Landau, M., Weizman, R., Weizman, A., 1999. Effects of psy-
chotropic drugs on cell proliferation and differentiation. Biochem. Pharmacol. 58,
1229–1236.
Ogra, Y., Tejima, A., Hatakeyama, N., Shiraiwa, M., Wu, S., Ishikawa, T., Yawata, A.,
Anan, Y., Suzuki, N., 2016. Changes in intracellular copper concentration and copper-
regulating gene expression after PC12 differentiation into neurons. Sci. Rep. 6, 1–9.
Okuyama, S., Nakazato, A., 1996. NE-100: a novel sigma receptor antagonist. CNS Drug
Rev. 2, 226–237.
Okuyama, S., Ogawa, S., Nakazato, A., Tomizawa, K., 1995. Effect of NE-100, a novel
sigma receptor ligand, on phencyclidine- induced delayed cognitive dysfunction in
rats. Neurosci. Lett. 189, 60–62.
Ressler, K., Nemeroff, C., 2000. Role of serotonergic and noradrenergic systems in the
pathophysiology of depression and anxiety disorders. Depress Anxiety 12, 2–19.
Rossi, D., Pedrali, A., Urbano, M., Gaggeri, R., Serra, M., Fernández, L., Fernández, M.,
Caballero, J., Ronsisvalle, S., Prezzavento, O., Schepmann, D., Wuensch, B., Peviani,
Y. Matsushima, et al.
M., Curti, D., Azzolina, O., Collina, S., 2011. Identification of a potent and selective
σ1 receptor agonist potentiating NGF-induced neurite outgrowth in PC12 cells.
Bioorg. Med. Chem. 19, 6210–6224.
Sangkuhl, K., Klein, T., Altman, R., 2009. Selective serotonin reuptake inhibitors (SSRI)
pathway. Pharm. Genom. 19, 907–909.
Setoguchi, S., Watase, D., Matsunaga, K., Yamakawa, H., Goto, S., Terada, K., Ohe, K.,
Enjoji, M., Karube, Y., Takata, J., 2018. Antitumor effects and delivery profiles of
menahydroquinone-4 prodrugs with ionic or nonionic promoiety to hepatocellular
carcinoma cells. Molecules 23, 1738.
Skuza, G., Rogó, Z., 2007. Antidepressant-like effect of combined treatment with selective
s receptor agonists and a 5-HT 1A receptor agonist in the forced swimming test in
rats. Pharmacol. Rep. 59, 773–777.
Sugimoto, Y., Tagawa, N., Kobayashi, Y., Mitsui-Saito, K., Hotta, Y., Yamada, J., 2012.
Involvement of the sigma1 receptor in the antidepressant-like effects of fluvoxamine
in the forced swimming test in comparison with the effects elicited by paroxetine.
Eur. J. Pharmacol. 696, 96–100.
Takebayashi, M., Hayashi, T., Su, T.-P., Unit, C.P., Neurobiology, C., 2002. Nerve growth
factor-induced neurite sprouting in PC12 cells involves σ-1 receptors: implications for
135
European Journal of Pharmacology 853 (2019) 129–135
antidepressants. Syst. Res. 303, 1227–1237.
Terada, K., Kojima, Y., Watanabe, T., Izumo, N., Chiba, K., Karube, Y., 2014. Inhibition of
nerve growth factor-induced neurite outgrowth from PC12 cells by dexamethasone:
signaling pathways through the glucocorticoid receptor and phosphorylated Akt and
ERK1/2. PLoS One 9, e93223.
Thakore, J.H., Berti, C., Dinan, T.G., 1996. An open trial of adjunctive sertraline in the
treatment of chronic schizophrenia. Acta Psychiatr. Scand. 94, 8891087.
Walker, J.M., Bowen, W.D., Walker, F.O., Matsumoto, R.R., De Costa, B., Rice, K.C., 1990.
Sigma receptors: biology and function. Pharmacol. Rev. 42, 355–402.
Wang, J., Mack, A.L., Coop, A., Matsumoto, R.R., 2007. Novel sigma (σ) receptor agonists
produce antidepressant-like effects in mice. Eur. Neuropsychopharmacol. 17,
708–716.
Wong, M.-L., Licinio, J., 2001. Research and treatment approaches to depression. Nat.
Rev. Neurosci. 2, 343–351.
Zhou, Z., Zhen, J., Karpowich, N.K., Law, C.J., Maarten, E.A., Wang, D., 2009.
Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI
structures. Nat. Struct. Mol. Biol. 16, 652–657.