Progress in Neuro-Psychopharmacology & Biological Psychiatry 65 (2016) 201–207

Contents lists available at ScienceDirect

Progress in Neuro-Psychopharmacology & Biological

Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Involvement of monoaminergic system in the antidepressant-like effect

of (octylseleno)-xylofuranoside in the mouse tail suspension test
Lucimar M. Pinto Brod a, Mariana G. Fronza b, Jaqueline Pinto Vargas c, Diogo S. Lüdtke c, Cristiane Luchese d,
Ethel Antunes Wilhelm d, Lucielli Savegnago a,⁎
a
Programa de Pós Graduação em Biotecnologia, PPGBiotec, Grupo de Pesquisa em Neurobiotecnologia — GPN, CDTec, Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil
b
Grupo de Pesquisa em Neurobiotecnologia — GPN, CDTec, Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil
c
Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, Av. Bento Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil
d
Programa de Pós Graduação em Bioquimica e Bioprospecção, PPGBBio, Grupo de Pesquisa em Neurobiotecnologia — GPN, CCQFA, Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Depression is one of the most commonly diagnosed neuropsychiatric disorders and several studies have demon-
Received 11 May 2015 strated a role for selenium in mood disorders. For this reason, the present study investigated the role of the mono-
Received in revised form 28 September 2015 aminergic system in the antidepressant-like action of (octylseleno)-xylofuranoside (OSX), an organoselenium
Accepted 23 October 2015
compound, in the tail suspension test (TST) in mice. For this purpose, OSX (0.001–10 mg/kg) was administered
Available online 24 October 2015
orally (p.o.) 30 min prior to testing, and all of the tested doses reduced the immobility time in the TST without
Keywords:
changing the locomotor activity measured in the open field test (OFT). Furthermore, the antidepressant-like
Selenium effect of OSX (0.01 mg/kg, p.o.) in the TST was prevented by pre-treatment in mice with ketanserin (1 mg/kg, in-
Antidepressant-like traperitoneal route (i.p.); a 5-HT2A/2C receptor antagonist), WAY100635 (0.1 mg/kg, subcutaneous (s.c.); a selec-
Organoselenium tive 5-HT1A receptor antagonist), p-chlorophenylalanine methyl ester-PCPA (100 mg/kg, i.p.; a selective inhibitor
of tryptophan hydroxylase), prazosin (1 mg/kg, i.p.; an α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p.;
an α2-adrenoceptor antagonist), SCH233390 (0.05 mg/kg, s.c., a dopaminergic D1 receptor antagonist) and
sulpiride (50 mg/kg, i.p., a dopaminergic D2 receptor antagonist), but not with ondansetron (1 mg/kg, i.p.; a se-
lective 5-HT3 receptor antagonist). Taken together, these data demonstrate that OSX has a potent antidepressant-
like effect in TST at lower doses (0.001–10 mg/kg), which is dependent on its interaction with the serotonergic,
noradrenergic and dopaminergic systems.
© 2015 Elsevier Inc. All rights reserved.

1. Introduction
Selenium is an essential trace element of fundamental importance to
human health, because it is the only one for which incorporation into
proteins is genetically encoded, as the constitutive part of the amino
acid selenocysteine (Roman et al., 2014). The selenocysteine form of
selenium is incorporated into selenoproteins, with physiological roles
including being structural components of several antioxidant enzymes
(Młyniec et al., 2015; Rayman, 2000; Roman et al., 2014; Ursini and
Bindoli, 1987), particularly the families of glutathione peroxidases
(GPxs) and thioredoxin reductases (TrxRs) (Roman et al., 2014).
Additionally, diminished levels of selenium in the brain are associat-
ed with cognitive decline (Ishrat et al., 2009) and studies have demon-
strated the role of selenium in mood disorders (Hawkes and Hornbostel,
1996; Sher, 2008). With regard to this, studies in adult and elderly
⁎ Corresponding author.
E-mail address: luciellisavegnago@yahoo.com.br (L. Savegnago).
populations have shown a higher risk of depression among those with
lower selenium intake (Pasco et al., 2012). Conner et al. (2015) sug-
gested that low selenium intake may be associated with a greater risk
of depressive symptomatology and negative mood, even among healthy
young adults. Depression is considered a complex, multifactorial, het-
erogeneous, and chronic mental disorder that affects ~120 million peo-
ple worldwide (Kessler and Bromet, 2013). Furthermore, depressives
have impairment of their activities and wellbeing, which leads to inca-
pability and loss of productivity, triggering a substantial social impact
(Ebmeier et al., 2006). The monoaminergic system is considered one
of the main targets in the pathophysiology and treatment of depression
(Elhwuegi, 2004; Millan, 2004). However, approximately 30% of pa-
tients do not respond to therapy with these drugs (Millan, 2009). There-
fore, other treatments should be considered, as they might provide
potential effective targets with higher efficacy for the treatment of de-
pression, and perhaps with fewer disadvantages.
In this context, several of the studies performed demonstrated the
antidepressant-like activity caused by organoselenium compounds, for
example, α-(phenylselanyl) acetophenone (Gerzson et al., 2012), 4-

http://dx.doi.org/10.1016/j.pnpbp.2015.10.008
0278-5846/© 2015 Elsevier Inc. All rights reserved.
202 L.M. Pinto Brod et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 65 (2016) 201–207
phenyl-1-(phenylselanylmethyl)-1,2,3-triazole (Donato et al., 2013),
α-phenylselenocitronellal (Victoria et al., 2014), bis selenide (Jesse
et al., 2010) and diphenyl diselenide (Savegnago et al., 2007).
Among the organoselenium compounds, the group of selenium-
containing carbohydrates has been investigated. For example,
arylseleno-furanosides and a carbohydrate-derived diselenide demon-
strated low toxicity and antioxidant effects (Braga et al., 2010; Vargas
et al., 2015). Additionally, selenoglycoside, another series of selenium-
containing carbohydrates, shows inhibitory effect in melanin synthesis
(Ahn et al., 2006). Moreover, arylseleno-furanoside therapy was effective
in restoring δ-ALA-D activity in ovaries that were inhibited by cadmium
(Vargas et al., 2013) and arylseleno- and aryltelluro-xylofuranosides
attenuate manganese-induced toxicity in Caenorhabditis elegans
(Wollenhaupt et al., 2014). In this regard, our research group investigated
the antioxidant activity profile of alkylseleno carbohydrates with differ-
ent sugar scaffolds, and the compound possessing a C8 alkyl chain
(octylseleno)-xylofuranoside (OSX) presented the best results in the
free radical scavenging activity (Vargas et al., 2015).
Therefore, based on the above considerations, our research group
sought to investigate the possible acute antidepressant-like effect of
the compound OSX in TST. In addition, the possible involvement of
serotoninergic, noradrenergic and dopaminergic systems in the
antidepressant-like activity of OSX in mice was evaluated.
2. Materials and methods
2.1. Animals
The experiments were conducted using male Swiss mice (25–35 g,
60–75 days) that were housed in groups (3–5 animals/cage) under
controlled conditions of light (from 07:00 to 19:00 h) and temperature
(22–25 °C). Each animal was used only once in each test and all exper-
iments were performed on separate groups of animals (n = 4–8
animals in each group). The animals were used according to the guide-
lines of the Committee on the Care and Use of Experimental Animal
Resources at the Federal University of Pelotas, Brazil (8967–2013). All
efforts were made to minimise animals' suffering and to reduce the
number of animals used in the experiments.
2.2. Drugs
The organoselenium compound, (octylseleno)-xylofuranoside (OSX,
Fig. 1) was synthesised in the Chemical Institute of the Federal Univer-
sity of Rio Grande do Sul, Brazil, and characterised by the previously
described method (Vargas et al., 2013). OSX was dissolved in canola
oil and was administered by oral route (p.o.) by gavage.
The following drugs were used: ketanserin, ondansetron, SCH23390,
p-chlorophenylalanine methyl ester (PCPA), prazosin, yohimbine,
WAY100635, sulpiride (Sigma Chemical Co, USA) and fluoxetine hydro-
chloride (Pfizer, Brazil). These drugs were diluted in saline 0.9% and
were injected via the intraperitoneal (i.p.) route, except fluoxetine,
which was administered by the oral route (p.o.) by gavage and
WAY100635, which was administered by the subcutaneous route
(s.c.). All drugs were administered in a constant volume of 10 ml/kg
body weight.
Fig. 1. Chemical structure of OSX.
2.3. Antidepressant-like effect of OSX in the tail suspension test (TST)
To assess the antidepressant-like effect of OSX, it was administered
only once (dose range 0.001–10 mg/kg) 30 min before the open field
test (OFT) and immediately after the same mice were assessed in the
TST. Fluoxetine (32 mg/kg) was used as a positive control and was
administered 30 min before the tests (Martinez et al., 2014).
2.4. Behavioural analysis
2.4.1. Tail suspension test (TST)
The total duration of immobility induced by TST was measured ac-
cording to the method described by Steru et al. (1985). Mice that were
both acoustically and visually isolated were suspended 50 cm above
the floor by adhesive tape placed approximately 1 cm from the tip of
their tail. Immobility time was recorded during a 6 min period. Mice
were considered immobile only when they hung passively and
completely motionless. The immobility time was recorded by observers
blind to the drug treatment (Cunha et al., 2008; Machado et al., 2009).
2.4.2. Open field test
To verify that the results obtained in the TST did not occur due to
changes in the motor activity of mice, the animals were analysed in
the OFT. After 30 min of compound administration, each animal was im-
mediately placed at the centre of the apparatus and observed for 5 min
to record locomotor (number of segments crossed with the four paws)
and exploratory activities (expressed by the number of time rearing on
the hind limbs) (Walsh and Cummins, 1976).
2.5. Mechanisms involved in the antidepressant-like effect of OSX
In another set of experiments, the role played by the serotoninergic
system in the antidepressant-like effect of OSX (0.01 mg/kg, p.o.) in the
TST was investigated. For this purpose, mice were pre-treated with
ketanserin (1 mg/kg, i.p.; a 5-HT2A/2C receptor antagonist),
WAY100635 (0.1 mg/kg, s.c.; a selective 5-HT1A receptor antagonist),
and ondansetron (1 mg/kg, i.p.; a 5-HT3 receptor antagonist) and
15 min later received vehicle (canola oil) or the compound
(0.01 mg/kg, p.o.). After 30 min of OSX or vehicle administration, the an-
imals were subjected to the OFT and TST. For complementing evaluation
of the serotoninergic system, animals were pre-treated with PCPA
(100 mg/kg, i.p., an inhibitor of serotonin synthesis) or vehicle, once a
day, for four consecutive days. Then, 24 h after the last PCPA or saline in-
jection, animals were treated with OSX (0.01 mg/kg, p.o.), or vehicle and
were tested in the OFT and TST 30 min later.
Moreover, to test the hypothesis that the antidepressant-like effect of
OSX is mediated through interaction with the noradrenergic system, the
animals were pre-treated with prazosin (1 mg/kg, i.p., an α1-
adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α2-adrenoceptor
antagonist) or vehicle; after 30 min, they received OSX (0.01 mg/kg,
p.o.), and after a further 30 min, mice were tested in the OFT and TST.
Also, to assess the possible involvement of the dopaminergic system in
the antidepressant-like effect of OSX, independent groups of animals
were pre-treated with SCH23390 (0.05 mg/kg, s.c., a dopaminergic D1 re-
ceptor antagonist), sulpiride (50 mg/kg, i.p., a dopaminergic D2 receptor
antagonist) or vehicle; after 1 h, they received OSX (0.01 mg/kg, p.o.) or
vehicle and were tested in the OFT and TST 30 min later. All doses of an-
tagonists used in this work were chosen according to previously pub-
lished data (Martinez et al., 2014; Savegnago et al., 2008).
2.6. Statistical analyses
All experimental results are given as the mean ± standard error of
the mean (S.E.M.). Comparisons between experimental and control
groups were performed by one-way (OSX treatment) or two-way
ANOVA (ketanserin, ondansetron, PCPA, prazosin, yohimbine,
 L.M. Pinto Brod et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 65 (2016) 201–207 203

SCH23390, sulpiride, WAY100635, and fluoxetine × OSX treatment)
followed by Newman–Keuls test for post hoc comparison when appro-
priate. A value of P ˂ 0.05 was considered to be significant.
3. Results
3.1. Effect of OSX on immobility time in TST and locomotor and exploratory
activities in OFT
treatment [F(1,27) = 3.58, P = 0.06]. The two way ANOVA revealed
no significant effect of OSX treatment [F(1,34) = 1.36; P = 0.25],
PCPA treatment [F(1,34) = 0.00; P = 0.95] and OSX × PCPA treatment
interaction [F(1,34) = 0.06; P = 0.80] to number of crossings. No signif-
icant effect for OSX treatment [F(1,34) = 0.35; P = 0.55], PCPA treat-
ment [F(1,34) = 1.40; P = 0.24] or OSX × PCPA interaction

The effect of OSX on immobility time in the TST was statistically sig-
nificant from 0.001–10 mg/kg when compared with the control group
(P b 0.001), as shown in Fig. 2A. OSX, given by p.o. route for all of the
doses tested did not produce any change in the number of crossings
and rearings of mice in the open field compared to the control group
(Fig. 2B and C).

3.2. Involvement of the serotonergic system on the antidepressant-like

effect of OSX

The results depicted in Fig. 3A show that pre-treatment with

ketanserin (a 5-HT2A/2C receptor antagonist) was able to prevent the re-
duction in immobility time elicited by OSX (0.01 mg/kg, p.o.). Two-way
ANOVA revealed a statistically significant effect of treatment with OSX
alone [F(1,34) = 46.79; P b 0.0001], ketanserin alone [F(1,34) = 8.23;
P = 0.0070] and treatment with ketanserin × OSX [F(1,34) = 4.27;
P = 0.0465]. No significant effect for OSX treatment [F(1,29) = 1.93,
P = 0.17], ketanserin treatment [F(1,29) = 0.01, P = 0.91] or OSX ×
ketanserin interaction [F(1,28) = 1.18, P = 0.28] on the number of
crossings, and no significant effect for OSX treatment [F(1,29) = 0.31,
P = 0.58], ketanserin treatment [F(1,29) = 2.23, P = 0.14] or OSX ×
ketanserin interaction [F(1,29) = 0.10, P = 0.75] on the number of
rearings in the open-field test was observed (Table 1).
On the other hand, pre-treatment with ondansetron (a 5-HT3 recep-
tor antagonist) was not able to prevent the reduction in immobility time
observed with OSX (0.01 mg/kg, p.o.) (Fig. 3B). Two-way ANOVA
revealed a statistically significant effect of treatment with OSX
[F(1,16) = 26.14; P = 0.0001] but not ondansetron × OSX [F(1,16) =
1.67; P = 0.21] and ondansetron [F(1,16) = 0.05; P = 0.819]. The two
way ANOVA revealed no significant effect of OSX treatment
[F(1,15) = 0.75; P = 0.40], ondansetron treatment [F(1,15) = 0.20;
P = 0.66] and OSX × ondansetron treatment interaction [F(1,15) =
0.25; P = 0.62] to number of crossings. No significant effect for OSX
treatment [F(1,15) = 0.64; P = 0.435], ondansetron treatment
[F(1,15) = 0; P = 0.99] or OSX × ondansetron interaction [F(1,15) =
0.86; P = 0.36] on the number of rearings in the open field test was
observed (Table 1).
The results in Fig. 3C show that the pre-treatment of mice with
WAY100635 (a selective 5-HT1A receptor antagonist) blocked the
reduction in the immobility time elicited by OSX (0.01 mg/kg, p.o.) in
the TST. Two-way ANOVA revealed a significant effect of OSX alone
[F(1,15) = 8.29, P = 0.011], WAY100635 alone [F(1,15) = 10.73, P =
0.005] and WAY100635 × OSX [F(1,15) = 7.42, P = 0.015]. Regarding
the open field test, none of the treatments altered the locomotor activity
of mice, two-way ANOVA revealed no significant effect for OSX treat-
ment [F(1,15) = 1.79, P = 0.20], WAY100635 treatment [F(1,15) =
0.00; P = 0.97] and OSX × WAY100635 treatment interaction
[F(1,15) = 0.53; P = 0.47] to number of crossings, and for OSX treat-
ment [F(1,16) = 1.43, P = 0.24], WAY100635 treatment [F(1,16) =
1.43; P = 0.24] and OSX × WAY100635 treatment interaction
[F(1,16) = 2.14; P = 0.16] to number of rearings in the open field test
(Table 1).
Moreover, this anti-immobility effect of OSX (0.01 mg/kg, p.o.) was
blocked by the pre-treatment of mice with the inhibitor of serotonin
Fig. 2. Effect of OSX (0.001–10 mg/kg, p.o.) administered in mice 30 min before on (A) the
synthesis, PCPA (Fig. 3D). A two-way ANOVA showed significant differ- tail suspension tail (TST), and open field test (B) crossings and (C) rearings. Values were
ences for OSX treatment [F(1,27) = 57.57, P b 0.0001], and PCPA × OSX expressed as the mean ± S.E.M. (n = 4–8). (***) P ˂ 0.001 in comparison to the vehicle
treatment interaction [F(1,27) = 6.89, P = 0.014] but not PCPA treated group.
204 L.M. Pinto Brod et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 65 (2016) 201–207

Fig. 3. Effect of pretreatment of mice with (A) ketanserin (1 mg/kg, i.p. a 5-HT2A/2C receptor antagonist); (B) ondansetron (1 mg/kg, i.p. a 5-HT3 receptor antagonist); (C) WAY100635
(0.1 mg/kg, s.c. a selective 5-HT1A receptor antagonist) and (D) PCPA (100 mg/kg, i.p., for 4 consecutive days, tryptophan hydroxylase inhibitor) on the anti-immobility effect of OSX
(0.01 mg/kg, p.o) in the TST. Data are presented as the mean ± S.E.M. (n = 4–8). (**) P ˂ 0.01 and (***) P ˂ 0.001 in comparison to the vehicle treated group (control); (#) P ˂ 0.05 compared
to OSX pretreated with vehicle.

[F(1,34) = 1; P = 0.32] on the number of rearings in the open field test

Table 1
Effect of administration of OSX and antagonists on behavioural parameters in the open was observed (Table 1).
field test in mice.

Experimental groups Number of Number of Number of

crossings rearings animals
3.3. Involvement of the noradrenergic system on the antidepressant-like
effect of OSX
Vehicle (saline 0.9%) 80.63 ± 1.56 20.38 ± 1.41 8
OSX (0.1 mg/kg) 70.25 ± 2.56 21.88 ± 1.35 8
Ketanserin (1 mg/kg) 75.60 ± 6.12 18.38 ± 1.75 5 Fig. 4A shows that the pre-treatment of mice with prazosin (an α1-
Ketanserin + OSX 74.33 ± 5.27 18.78 ± 2.06 8 adrenoceptor antagonist) prevented the antidepressant-like effect of
Vehicle (saline 0.9%) 92.40 ± 4.13 23.25 ± 2.01 5 OSX (0.01 mg/kg, p.o.) in the TST. The two-way ANOVA revealed signif-
OSX (0.1 mg/kg) 101.5 ± 11.29 21.50 ± 2.90 4
icant differences of OSX treatment [F(1,16) = 14.78, P = 0.0014] and
Ondansetron (1 mg/kg) 92.80 ± 1.53 19.20 ± 2.39 5
Ondansetron + OSX 95.20 ± 7.72 24.60 ± 2.18 5
prazosin × OSX treatment interaction [F(1,16) = 7.35, P = 0.015] but
Vehicle (saline 0.9%) 79.20 ± 10.58 19.80 ± 2.87 5 not prazosin treatment [F(1,16) = 0.01, P = 0.92]. No significant effect
OSX (0.1 mg/kg) 75.20 ± 3.96 19.20 ± 2.39 5 for OSX treatment [F(1,16) = 1.52, P = 0.23], prazosin treatment
WAY100635 (0.1 mg/kg) 83.75 ± 3.70 19.20 ± 1.88 4 [F(1,16) = 0.00, P = 0.98] or OSX × prazosin interaction [F(1,16) =
WAY100635 + OSX 70.20 ± 4.00 25.20 ± 1.68 5
2.2, P = 0.16] on the number of crossings, and no significant effect for
Vehicle (saline 0.9%) 88.40 ± 2.59 28.20 ± 4.49 8
OSX (0.1 mg/kg) 84.50 ± 5.90 22.20 ± 2.47 8 OSX treatment [F(1,16) = 2.03, P = 0.17], prazosin treatment
PCPA (100 mg/kg) 88.50 ± 4.61 28.90 ± 2.79 8 [F(1,29) = 0.12, P = 0.73] or OSX × prazosin interaction [F(1,29) =
PCPA + OSX 86.00 ± 5.05 30.43 ± 5.25 7 0.00, P = 1.00] on the number of rearings in the open-field test was ob-
Vehicle (saline 0.9%) 84.40 ± 1.20 22.00 ± 0.70 5
served (Table 1).
OSX (0.1 mg/kg) 72.40 ± 6.16 17.80 ± 3.86 5
Prazosin (1 mg/kg) 77.80 ± 5.78 23.00 ± 2.84 5
Fig. 4B shows that the pre-treatment of mice with yohimbine (an
Prazosin + OSX 78.80 ± 2.59 18.80 ± 3.33 5 α2-adrenoceptor antagonist) blocked the reduction in the immobil-
Vehicle (saline 0.9%) 79.20 ± 10.58 19.80 ± 2.87 5 ity time elicited by OSX (0.01 mg/kg, p.o.) in the TST. Two-way
OSX (0.1 mg/kg) 74.00 ± 4.18 25.80 ± 2.70 5 ANOVA revealed a significant effect of OSX alone [F(1,14) = 10.98,
Yohimbine (1 mg/kg) 74.20 ± 6.53 20.00 ± 3.60 5
P = 0.005], yohimbine × OSX treatment interaction [F(1,14) =
Yohimbine + OSX 51.20 ± 5.32 17.50 ± 3.12 5
Vehicle (saline 0.9%) 76.60 ± 2.42 22.00 ± 0.70 5 8.28, P = 0.012], but not yohimbine alone [F(1,14) = 3.72, P =
OSX (0.1 mg/kg) 78.60 ± 4.29 17.80 ± 3.86 5 0.074]. The administration of yohimbine alone or in combination
SCH233390 (0.05 mg/kg) 82.25 ± 3.92 19.75 ± 0.94 4 with OSX did not affect (P ˃ 0.05) the ambulation in the open-field
SCH233390 + OSX 72.20 ± 6.96 20.00 ± 2.91 5
(Table 1). The two way ANOVA revealed no significant effect of OSX
Vehicle (saline 0.9%) 64.14 ± 4.67 22.86 ± 2.96 7
OSX (0.1 mg/kg) 51.25 ± 7.77 23.83 ± 3.73 4
treatment [F(1,16) = 3.97; P = 0.06], yohimbine treatment
Sulpiride (50 mg/kg) 57.60 ± 11.14 28.00 ± 4.52 5 [F(1,16) = 3.86; P = 0.06] and OSX × yohimbine treatment interac-
Sulpiride + OSX 57.00 ± 6.26 28.17 ± 3.13 7 tion [F(1,16) = 1.58; P = 0.2] to number of crossings. No significant
The effect of mice behavioural on the open field test was determined by two-way ANOVA effect for OSX treatment [F(1,13) = 0.97; P = 0.34], yohimbine treat-
followed by Newman-Keuls test. Data presented are mean values ± S.E.M. (n = 4–8). ment [F(1,13) = 3.28; P = 0.09] or OSX × yohimbine interaction
 L.M. Pinto Brod et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 65 (2016) 201–207
Fig. 4. Effect of pretreatment of mice with (A) prazosin (1 mg/kg, i.p. an α1-adrenoceptor
antagonist) and (B) yohimbine (1 mg/kg, i.p. an α2-adrenoceptor antagonist) on the anti-
immobility effect of OSX (0.01 mg/kg, p.o) in the TST. Data are presented as the mean ±
S.E.M. (n = 4–8). (**) P ˂ 0.01 in comparison to the vehicle treated control; (#) P ˂ 0.05
compared to OSX pretreated with vehicle.
[F(1,13) = 3.55; P = 0.08] on the number of rearings in the open
field test was observed.
3.4. Involvement of the dopaminergic system on the antidepressant-like
effect of OSX
Results illustrated in Fig. 5A show that the pre-treatment of mice
with SCH233390 (a dopaminergic D1 receptor antagonist), was able to
abolish the antidepressant-like effect of OSX (0.01 mg/kg, p.o.) in the
TST. The two-way ANOVA revealed significant differences of OSX treat-
ment [F(1,15) = 8.84, P = 0.009], SCH233390 treatment [F(1,15) =
45.85, P ˂ 0.0001] and SCH233390 × OSX treatment interaction
[F(1,15) = 71.88, P ˂ 0.0001]. No significant effect of treatments in loco-
motor activity in the open-field test was observed (Table 1). No signifi-
cant effect for OSX treatment [F(1,15) = 0.70, P = 0.41], SCH233390
treatment [F(1,15) = 0.01, P = 0.93] or OSX × SCH233390 interaction
[F(1,16) = 1.56, P = 0.23] on the number of crossings, and no signifi-
cant effect for OSX treatment [F(1,14) = 0.58, P = 0.46], SCH233390
treatment [F(1,14) = 0.00, P = 0.99] or OSX × SCH233390 interaction
[F(1,14) = 0.73, P = 0.40] on the number of rearings in the open-field
test was observed.
Pre-treatment of mice with sulpiride (a dopaminergic D2 receptor
antagonist), blocked the antidepressant-like effect of OSX (0.01 mg/kg,
p.o.) in the TST. The two-way ANOVA revealed significant differences
of OSX treatment [F(1,16) = 18.62, P = 0.0005], sulpiride treatment
[F(1,16) = 25.21, P = 0.0001] and sulpiride × OSX treatment interac-
tion [F(1,16) = 19.24, P = 0.0005]. The two way ANOVA revealed no
significant effect of OSX treatment [F(1,19) = 0.81; P = 0.37], sulpiride
treatment [F(1,19) = 0; P = 0.95] and OSX × sulpiride treatment inter-
action [F(1,19) = 0.68; P = 0.42] to number of crossings. No significant
effect for OSX treatment [F(1,21) = 0.03; P = 0.87], sulpiride treatment
[F(1,21) = 1.73 P = 0.20] or OSX × sulpiride interaction [F(1,21) =
205
Fig. 5. Effect of pretreatment of mice with (A) SCH233390 (0.05 mg/kg, s.c., a dopaminer-
gic D1 receptor antagonist) and (B) Sulpiride (50 mg/kg, i.p., a dopaminergic D2 receptor
antagonist) on the anti-immobility effect of OSX (0.01 mg/kg, p.o) in the TST. Data are pre-
sented as the mean ± S.E.M. (n = 4–8). (***) P ˂ 0.001 in comparison to the vehicle treated
control; (#) P ˂ 0.0001 compared to OSX pretreated with vehicle.
0.01; P = 0.91] on the number of rearings in the open field test was ob-
served (Table 1).
4. Discussion
In this study, it was demonstrated that OSX produced a significant
antidepressant-like effect at all of the doses tested (0.001–10 mg/kg)
in TST in mice. Importantly, none of the treatments caused changes in
the spontaneous locomotion of mice, indicating that the results obtain-
ed in the TST were not due to any non-specific changes in locomotor
activity.
In this study, at the lowest dose tested, OSX already had a significant
antidepressant-like effect in TST compared with others organoselenium
compounds, such as, diphenyl diselenide (5–100 mg/kg; p.o.)
(Savegnago et al., 2008), ebselen (10–30 mg/kg s.c.) (Posser et al.,
2009), α-(phenylselanyl) acetophenone (0.1–10 mg/kg, p.o) (Gerzson
et al., 2012), α-phenylselenocitronellal (1–100 mg/kg, p.o.) (Victoria
et al., 2014), 4-phenyl-1-(phenylselanylmethyl)-1,2,3-triazole (1–
50 mg/kg, p.o.) (Donato et al., 2013), m-trifluoromethyl diphenyl
diselenide (1–50 mg/kg, p.o.) (Brüning et al., 2014) and 2,5-diphenyl-
3-(4-fluorophenylseleno)-selenophene (25–50 mg/kg, p.o.) (Gai et al.,
2014).
Herein we observed that the antidepressant-like effect of OSX is
probably due to modulation of the serotonergic, noradrenergic and do-
paminergic systems. Regarding the serotoninergic system, there are
several lines of evidence reporting that drugs that affect serotonin neu-
rotransmission, such as those inhibiting 5-HT reuptake at nerve termi-
nals or inhibiting monoamines metabolism (MAO inhibitors), are
effective in the treatment of depression (Elhwuegi, 2004). In order to in-
vestigate a possible contribution of the serotonergic system in the OSX
antidepressant-like action, different 5-HT receptor antagonists were
tested. In fact, 5-HT receptors it is well known that the mechanism of
action of several classes of antidepressant drugs, such as tricyclics,
monoamine oxidase inhibitors and SSRIs occur by the participation of
the 5-HT1A (Hensler, 2006), 5-HT2A and 5-HT2C receptors (Artigas,
206 L.M. Pinto Brod et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 65 (2016) 201–207
2013). In this study, the pre-treatment of mice with WAY100635 (a se-
lective 5-HT1A receptor antagonist) abolished OSX antidepressant-like
effect, thus demonstrating the 5-HT1A receptor participation in such ef-
fect. The involvement of 5-HT2A/C receptor in the antidepressant-like ef-
fect of OSX was demonstrated since the pre-treatment of mice with
ketanserin (a 5-HT2A/C receptor antagonist) was able to abolish OSX
anti-immobility effect. Considering that ketanserin has a higher affinity
for 5-HT2A than to 5-HT2C receptor subtype (Glennon et al., 2002) we
suggest that OSX effect in the TST is mediated through an interaction
with 5-HT2A although the participation of 5-HT2C cannot be ruled out.
To further explore the role of the serotonergic system in the OSX
antidepressant-like action, PCPA, a selective inhibitor of the rate-
limiting enzyme in the biosynthesis of serotonin, tryptophan hydroxy-
lase, was the approach used to deplete endogenous brain serotonin
(Koe and Weissman, 1966). PCPA was reported to produce a significant
depletion of cortical 5-HT content in rats (93%) and mice (67–70%)
(Cesana et al., 1993; O'Leary et al., 2007; Page et al., 1999). The results
presented here demonstrated that PCPA treatment was able prevent
the antidepressant-like effect of OSX in TST, indicating that its
antidepressant-like effect is dependent on the availability of serotonin
in the synaptic cleft.
In parallel with the serotonergic system, involvement of the noradren-
ergic system is also suggested in the pathophysiology of depression
(Dailly et al., 2004; Dunlop and Nemeroff, 2007). The hypofunction of
the noradrenergic system seems to be associated with depression
(Brunello et al., 2003; Wang et al., 1999) and some antidepressants such
as reboxetine and mirtazapine act by increasing the synaptic availability
of noradrenaline (Brunello et al., 2003; Cardoso et al., 2009). In this
study, the pre-treatment of mice with prazosin (an α1-adrenoreceptor
antagonist) and yohimbine (an α2-adrenoreceptor antagonist) has
blocked the antidepressant-like effect of OSX. This finding indicates that
the noradrenergic system is also involved in the action of OSX.
In the present study, we also observed that the selective dopamine
D1 receptor antagonist SCH23390, and the dopamine D2 receptor antag-
onist sulpiride, were able to block the anti-immobility effects of OSX in
the TST. Thus, we assume that could OSX facilitate the dopaminergic
neurotransmission, leading to the indiscriminate activation of all dopa-
minergic receptors in brains of mice. Clinical studies showed that the
plasma levels of dopamine metabolites were significantly lower in the
depressed patients, indicating a diminished dopamine turnover
(Mitani et al., 2006; Sher et al., 2006). In this sense, there is also a con-
siderable amount of pharmacological evidence regarding the efficacy
of antidepressants with dopaminergic effects in the treatment of de-
pression (Papakostas, 2006), e.g. bupropion (Dhillon et al., 2008) and
imipramine (Hirano et al., 2007).
After obtaining the results discussed so far, we conclude that brain
monoamines should be sustained at a certain level to maintain OSX
antidepressant-like response, consistent with the notion that serotoner-
gic, noradrenergic and dopaminergic systems concur in the therapeutic
antidepressant efficacy (Hamon and Blier, 2013). In this sense, drugs
inhibiting the uptake of serotonin, noradrenaline, and dopamine (triple
reuptake inhibitors) that have been developed could produce a more
rapid onset of action and own greater efficacy than over single or dual
reuptake inhibitor antidepressants (Chen and Skolnick, 2007; Liang
et al., 2008).
In this study, the exact mechanism by which OSX modulates the
monoaminergic system is rather unclear. Serotoninergic receptors
take their physiologic effects by affecting adenylyl cyclase catalytic ac-
tivity and cyclic adenosine monophosphate (cAMP) concentration
(Marsden, 2013). Adenylyl cyclase–cAMP second messenger pathway
has been suggested to play an important role in depression (Li et al.,
2009). Therefore it is possible that the compounds like OSX may regu-
late the adenylyl cyclase- cAMP signal pathway which needs to be stud-
ied. Evidence also shows that increased BDNF has potent neurotrophic
effects on a wide range of neuronal populations (Li et al., 2013;
Manosso et al., 2015). Notably, BDNF is a downstream effect of increased
serotonin/norepinephrine neurotransmission. Taking into account the
above, more studies are needed to conclude the mechanism of action
of the OSX involved in its antidepressant-like effect. Thus, it could be
hypothesised that OSX might exert antidepressant-like activity by regu-
lating the interaction between the monoaminergic system and BDNF
which was not investigated in this study.
A recent study performed by our group showed the synthesis and
antioxidant activity of OSX (Vargas et al., 2015). Although the mecha-
nisms provoking depression have not been clearly elucidated, oxidative
stress, in the form of free radical production, may play an important role
in its pathophysiology (Eren et al., 2007). It is likely that oxidative stress
is primarily or secondarily involved in the pathogenesis of major de-
pression. Thus, drugs with potential antioxidant action could be attrac-
tive targets for the treatment of depressive disorders (Eren et al., 2007;
Zafir et al., 2009). This hypothesis is also reinforced by the fact that some
antidepressants have antioxidant effects (Behr et al., 2012) and other
antioxidants (e.g. ascorbic acid, green tea polyphenols, ebselen) have
been reported to exert antidepressant-like effects (Ferreira et al.,
2008; Moretti et al., 2011, 2012, Posser et al., 2009). Therefore, consis-
tent with this assumption, several preclinical and clinical studies have
shown that intracellular signalling pathways are targets for the actions
of antidepressant agents (Kitagishi et al., 2012; Marsden, 2013). Howev-
er, it is not possible to draw more concrete conclusions regarding the
roles of antioxidants in the behavioural responses of mice treated with
OSX; therefore, further studies are necessary to confirm and extend
these results. Finally, we speculate that OSX might be of interest as an
antioxidant or antidepressant agent for the treatment of depression.
Therefore, based on the above report, we can infer that the com-
pound OSX can be considered new and attractive strategy for the man-
agement of depression.
5. Conclusion
In summary, the results of this study show an involvement of the
serotonergic, noradrenergic and dopaminergic systems in the
antidepressant-like effect elicited by the oral administration of OSX in
TST in mice. In this sense, more studies are necessary to investigate
other mechanisms involved in the OSX antidepressant-like effect, and
their possible synergistic effect with available conventional
antidepressants.
Acknowledgments
The project was supported by Coordenação de Aperfeiçoamento de
Pessoal de nível Superior (CAPES), CNPq (#446455/2014-8, #306824/
2013-2) and FAPERGS (#2012-2551/13-8).
References
Ahn, S.J., Koketsu, M., Ishihara, H., Lee, S.M., Ha, S.K., Lee, K.H., Kang, T.H., Kima, S.Y., 2006.
Regulation of melanin synthesis by selenium-containing carbohydrates. Chem.
Pharm. Bull. 54, 281–286.
Artigas, F., 2013. Serotonin receptors involved in antidepressant effects. Pharmacol. Ther.
137, 119.
Behr, G.A., Moreira, J.C., Frey, B.N., 2012. Preclinical and clinical evidence of antioxidant ef-
fects of antidepressant agents: implications for the pathophysiology of major depres-
sive disorder. Oxidative Med. Cell. Longev. 2012, 609421.
Braga, H.C., Stefani, H.A., Paixão, M.W., Santos, F.W., Lüdtke, D.S., 2010. Synthesis of 5′-
seleno-xylofuranosides. Tetrahedron 66, 34–41.
Brunello, N., Blier, P., Judd, L.L., Mendlewicz, J., Nelson, C.J., Souery, D., Zohar, J., Racagni, G.,
2003. Noradrenaline in mood and anxiety disorders: basic and clinical studies. Int.
Clin. Psychopharmacol. 18, 191–202.
Brüning, C.A., Gai, B.M., Soares, S.M., Martini, F., Nogueira, C.W., 2014. Serotonergic sys-
tems are implicated in antinociceptive effect of m-trifluoromethyl diphenyl
diselenide in the mouse glutamate test. Pharmacol. Biochem. Behav. 125, 15–20.
Cardoso, C.C., Lobato, K.R., Binfaré, R.W., Ferreira, P.K., Rosa, A.O., Santos, A.R., Rodrigues,
A.L., 2009. Evidence for the involvement of the monoaminergic system in the
antidepressant-like effect of magnesium. Prog. Neuro-Psychopharmacol. Biol. Psychi-
atry 33, 235–242.
 L.M. Pinto Brod et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 65 (2016) 201–207
Cesana, R., Ceci, A., Ciprandi, C., Borsini, F., 1993. Mesulergine antagonism towards the flu-
oxetine anti-immobility effect in the forced swimming test in mice. J. Pharm.
Pharmacol 45, 473–475.
Chen, Z., Skolnick, P., 2007. Triple uptake inhibitors: therapeutic potential in depression
and beyond. Expert Opin. Investig. Drugs 16, 1365–1377.
Conner, T.S., Richardson, A.C., Miller, J.C., 2015. Optimal serum selenium concentrations
are associated with lower depressive symptoms and negative mood among young
adults. J. Nutr. 145, 59–65.
Cunha, M.P., Machado, D.G., Bettio, L.E.B., Capra, J.C., Rodrigues, A.L.S., 2008. Interaction of
zinc with antidepressants in the tail suspension test. Prog. Neuro-Psychopharmacol.
Biol. Psychiatry 32, 1913–1920.
Dailly, E., Chenu, F., Renard, C.E., Bourin, M., 2004. Dopamine, depression and antidepres-
sants. Fundam. Clin. Pharmacol. 18, 601–607.
Dhillon, S., Yang, L.P., Curran, M.P., 2008. Bupropion: a review of its use in the manage-
ment of major depressive disorder. Drugs 68, 653–689.
Donato, F., de Gomes, M.G., Goes, A.T., Seus, N., Alves, D., Jesse, C.R., Savegnago, L., 2013.
Involvement of the dopaminergic and serotonergic systems in the antidepressant-
like effect caused by 4-phenyl-1-(phenylselanylmethyl)-1,2,3-triazole. Life Sci. 93,
393–400.
Dunlop, B.W., Nemeroff, C.B., 2007. The role of dopamine in the pathophysiology of de-
pression. Arch. Gen. Psychiatry 64, 327–337.
Ebmeier, K.P., Donaghey, C., Steele, J.C., 2006. Recent developments and current contro-
versies in depression. Lancet 367, 153–167.
Elhwuegi, A.S., 2004. Central monoamines and their role in major depression. Prog.
Neuro-Psychopharmacol. Biol. Psychiatry 28, 435–451.
Eren, I., Naziroğlu, M., Demirdaş, A., 2007. Protective effects of lamotrigine, aripiprazole
and escitalopram on depression-induced oxidative stress in rat brain. Neurochem.
Res. 32, 1188–1195.
Ferreira, F.R., Biojone, C., Joca, S.R., Guimarães, F.S., 2008. Antidepressant-like effects of N-
acetyl-L-cysteine in rats. Behav. Pharmacol. 19, 747–750.
Gai, B.M., Sanna, M.D., Stein, A.L., Zeni, G., Galeotti, N., Nogueira, C.W., 2014. ERK1/2 phos-
phorylation is involved in the antidepressant-like action of 2,5-diphenyl-3-(4-
fluorophenylseleno)-selenophene in mice. Eur. J. Pharmacol. 736, 44–54.
Gerzson, M.F.B., Victoria, F.N., Radatz, C.S., de Gomes, M.G., Boeira, S.P., Jacob, R., Alves, D.,
Jesse, C.R., Savegnago, L., 2012. In vitro antioxidant activity and in vivo
antidepressant-like effect of - (phenylselanyl) acetophenone in mice. Pharmacol.
Biochem. Behav. 102, 21–29.
Glennon, R.A., Metwally, K., Dukat, M., Ismaiel, A.M., De los Angeles, J., Herndon, J., et al.,
2002. Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antago-
nists. Curr. Top. Med. Chem. 2, 539–558.
Hamon, M., Blier, P., 2013. Monoamine neurocircuitry in depression and strategies for
new treatments. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 45, 54–63.
Hawkes, W.C., Hornbostel, L., 1996. Effects of dietary selenium on mood in healthy men
living in a metabolic research unit. Biol. Psychiatry 2, 121–128.
Hensler, J.G., 2006. Serotonergic modulation of the limbic system. Neurosci. Biobehav.
Rev. 30, 203–214.
Hirano, S., Miyata, S., Onodera, K., Kamei, J., 2007. Involvement of dopamine D1 receptors
and α1-adrenoceptors in the antidepressant-like effect of chlorpheniramine in the
mouse tail suspension test. Eur. J. Pharmacol. 562, 72–76.
Ishrat, T., Parveen, K., Khan, M.M., Khuwaja, G., Khan, M.B., Yousuf, S., Ahmad, A.,
Shrivastav, P., Islam, F., 2009. Selenium prevents cognitive decline and oxidative
damage in rat model of streptozotocin-induced experimental dementia of
Alzheimer's type. Brain Res. 1281, 117–127.
Jesse, C.R., Wilhelm, E.A., Bortolatto, C.F., Rocha, J.B., Nogueira, C.W., 2010. Involvement of
L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the
antidepressant-like effect of bis selenide in the mouse tail suspension test. Eur.
J. Pharmacol. 635, 135–141.
Kessler, R.C., Bromet, E.J., 2013. The epidemiology of depression across cultures. Annu.
Rev. Public Health 34, 119–138.
Kitagishi, Y., Kobayashi, M., Kikuta, K., Matsuda, S., 2012. Roles of PI3K/AKT/GSK3/mTOR
pathway in cell signaling of mental illnesses. Depress. Res. Treat. 2012, 752563.
Koe, B.K., Weissman, A., 1966. p-chlorophenylalanine: a specific depletor of brain seroto-
nin. J. Pharmacol. Exp. Ther. 154, 499–516.
Li, Y.C., Wang, F.M., Pa, Y., Qiang, L., Cheng, G., Zhang, W.Y., Kong, L.D., 2009.
Antidepressant-like effects of curcumin on serotonergic receptor-coupled AC–cAMP
pathway in chronic unpredictable mild stress of rats. Prog. Neuro-
Psychopharmacol. Biol. Psychiatry 33, 435–449.
Li, Y.J., Xu, M., Gao, Z., Wang, Y.Q., Yue, Z., Zhang, Y.X., Li, X.X., Zhang, C., Xie, S.Y., Wang,
P.Y., 2013. Alterations of serum levels of BDNF-related miRNAs in patients with de-
pression. PLoS One 8, 1–7.
Liang, Y., Shaw, A.M., Boules, M., Briody, S., Robinson, J., Oliveros, A., Blazar, E., Williams, K.,
Zhang, Y., Carlier, P.R., Richelson, E., 2008. Antidepressant-like pharmacological pro-
file of a novel triple reuptake inhibitor, (1S,2S)-3-(methylamino)-2-(naphthalen-2-
yl)-1-phenylpropan-1-ol (PRC200-SS). J. Pharmacol. Exp. Ther. 27, 573–583.
Machado, D.G., Bettio, L.E., Cunha, M.P., Capra, J.C., Dalmarco, J.B., Pizzolatti, M.G.,
Rodrigues, A.L., 2009. Antidepressant-like effect of the extract of Rosmarinus officinalis
in mice: involvement of the monoaminergic system. Prog. Neuro-Psychopharmacol.
Biol. Psychiatry 33, 642–650.
Manosso, L.M., Moretti, M., Ribeiro, C.M., Gonçalves, F.M., Leal, R.B., Rodrigues, A.L.,
2015. Antidepressant-like effect of zinc is dependent on signaling pathways
207
implicated in BDNF modulation. Prog. Neuro-Psychopharmacol. Biol. Psychiatry
59, 59–67.
Marsden, W.N., 2013. Synaptic plasticity in depression: molecular, cellular and functional
correlates. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 43, 168–184.
Martinez, D.M., Barcellos, A., Casaril, A.M., Savegnago, L., Lernardão, E.J., 2014.
Antidepressant-like activity of dehydrozingerone: involvement of the serotonergic
and noradrenergic systems. Pharmacol. Biochem. Behav. 127, 111–117.
Millan, M.J., 2004. The role of monoamines in the actions of established and "novel" anti-
depressant agents: a critical review. Eur. J. Pharmacol 500, 371–384.
Millan, M.J., 2009. Dual- and triple-acting agents for treating core and co-morbid symp-
toms of major depression: novel concepts, new drugs. Neurotherapeutics 6, 53–77.
Mitani, H., Shirayama, Y., Yamada, T., Kawahara, R., 2006. Plasma levels of homovanillic
acid, 5-hydroxyindoleacetic acid and cortisol, and serotonin turnover in depressed
patients. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 30, 531–534.
Młyniec, K., Gaweł, M., Doboszewska, U., Starowicz, G., Pytka, K., Davies, C.L.,
Budziszewska, B., 2015. Essential elements in depression and anxiety. Part II.
Pharmacol. Rep. 67, 187–194.
Moretti, M., Colla, A., de Oliveira, B.G., dos Santos, D.B., Budni, J., de Freitas, A.E., Farina, M.,
Severo Rodrigues, A.L., 2012. Ascorbic acid treatment, similarly to fluoxetine, reverses
depressive-like behavior and brain oxidative damage induced by chronic unpredict-
able stress. J. Psychiatr. Res. 46, 331–340.
Moretti, M., Freitas, A.E., Budni, J., Fernandes, S.C., Balen Gde, O., Rodrigues, A.L., 2011. In-
volvement of nitric oxide-cGMP pathway in the antidepressant-like effect of ascorbic
acid in the tail suspension test. Behav. Brain Res. 225, 328–333.
O’Leary, O.F., Bechtholt, A.J., Crowley, J.J., Hill, T.E., Page, M.E., Lucki, I., 2007. Depletion of
serotonin and catecholamines block the acute behavioral response to different classes
of antidepressant drugs in the mouse tail suspension test. Psychopharmacology 192,
357–371.
Page, M.E., Detke, M.J., Dalvi, A., Kirby, L.G., Lucki, I., 1999. Serotonergic mediation of the
effects of fluoxetine, but not desipramine, in the rat forced swimming test. Psycho-
pharmacology 147, 162–167.
Papakostas, G.I., 2006. Dopaminergic-based pharmacotherapies for depression. Eur.
Neuropsychopharmacol. 16, 391–402.
Pasco, J.A., Jacka, F.N., Williams, L.J., Evans-Cleverdon, M., Brennan, S.L., Kotowicz
Nicholson, G.C., Ball, M.J., Berk, M., 2012. Dietary selenium and major depression: a
nested case–control study. Complement. Ther. Med. 20, 119–123.
Posser, T., Kaster, M.P., Baraúna, S.C., Rocha, J.B., Rodrigues, A.L., Leal, R.B., 2009.
Antidepressant-like effect of the organoselenium compound ebselen in mice: evi-
dence for the involvement of the monoaminergic system. Eur. J. Pharmacol. 602,
85–91.
Rayman, M.P., 2000. The importance of selenium to human health. Lancet 356, 233–241.
Roman, M., Jitaru, P., Barbante, C., 2014. Selenium biochemistry and its role for human
health. Metallomics 6, 25–54.
Savegnago, L., Jesse, C.R., Pinto, L.G., Rocha, J.B., Barancelli, D.A., Nogueira, C.W., Zeni, G.,
2008. Diphenyl diselenide exerts antidepressant-like and anxiolytic-like effects in
mice: involvement of L-arginine-nitric oxide-soluble guanylate cyclase pathway in
its antidepressant-like action. Pharmacol. Biochem. Behav. 88, 418–426.
Savegnago, L., Jesse, C.R., Pinto, L.G., Rocha, J.B.T., Nogueira, C.W., Zeni, G., 2007. Monoam-
inergic agents modulate antidepressant-like effect caused by diphenyl diselenide in
rats. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 31, 1261–1269.
Sher, L., 2008. Depression and suicidal behavior in alcohol abusing adolescents: possible
role of selenium deficiency. Minerva Pediatr. 60, 201–209.
Sher, L., Mann, J.J., Traskman-Bendz, L., Winchel, R., Huang, Y.Y., Fertuck, E., Stanley, B.H.,
2006. Lower cerebrospinal fluid homovanillic acid levels in depressed suicide
attempters. J. Affect. Disord. 90, 83–89.
Steru, L., Chermat, R., Thierry, B., Simon, P., 1985. The tail suspension test: a new method
for screening antidepressants in mice. Psychopharmacology 85, 367–370.
Ursini, F., Bindoli, A., 1987. The role of selenium peroxidases in the protection against ox-
idative damage of membranes. Chem. Phys. Lipids 44, 255–276.
Vargas, J.P., Pinto, L.M., Savegnago, L., Lüdtke, D.S., 2015. Synthesis of alkylseleno-carbohy-
drates and evaluation of their antioxidant properties. J. Braz. Chem. Soc. 00, 1–6.
Vargas, L.M., Soares, M.B., Izaguirry, A.P., Lüdtke, D.S., Braga, H.C., Savegnago, L.,
Wollenhaupt, S., Brum Ddos, S., Leivas, F.G., Santos, F.W., 2013. Cadmium inhibits
the ovary δ-aminolevulinate dehydratase activity in vitro and ex vivo: protective
role of seleno-furanoside. J. Appl. Toxicol. 33, 679–684.
Victoria, F.N., Anversa, R., Penteado, F., Castro, M., Lenardão, E.J., Savegnago, L., 2014. An-
tioxidant and antidepressant-like activities of semi-synthetic α-phenylseleno citro-
nellal. Eur. J. Pharmacol. 742, 131–138.
Walsh, R.N., Cummins, R.A., 1976. The open-field test: a critical review. Psychol. Bull. 83,
482–504.
Wang, Y.M., Xu, F., Gainetdinov, R.R., Caron, M.G., 1999. Genetic approaches to studying
norepinephrine function: knockout of the mouse norepinephrine transporter gene.
Biol. Psychiatry 46, 1124–1130.
Wollenhaupt, S.G., Soares, A.T., Salgueiro, W.G., Noremberg, S., Reis, G., Viana, C., Gubert,
P., Soares, F.A., Affeldt, R.F., Lüdtke, D.S., Santos, F.W., Denardin, C.C., Aschner, M.,
Avila, D.S., 2014. Seleno- and telluro-xylofuranosides attenuate Mn-induced toxicity
in C. elegans via the DAF-16/FOXO pathway. Food Chem. Toxicol. 64, 192–199.
Zafir, A., Ara, A., Banu, N., 2009. Invivo antioxidant status: a putative target of antidepres-
sant action. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 33, 220–228.