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Involvement of monoaminergic system in the antidepressant-like effect of (octylseleno)-xylofuranoside in the mouse tail suspension test
Progress in Neuro-Psychopharmacology & Biological Psychiatry 65 (2016) 201–207
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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 Grupo de Pesquisa em Neurobiotecnologia — GPN, CDTec, Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil 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 b c
a r t i c l e
i n f o
Article history: Received 11 May 2015 Received in revised form 28 September 2015 Accepted 23 October 2015 Available online 24 October 2015 Keywords: Selenium Antidepressant-like Organoselenium
a b s t r a c t Depression is one of the most commonly diagnosed neuropsychiatric disorders and several studies have demonstrated a role for selenium in mood disorders. For this reason, the present study investigated the role of the monoaminergic system in the antidepressant-like action of (octylseleno)-xylofuranoside (OSX), an organoselenium compound, in the tail suspension test (TST) in mice. For this purpose, OSX (0.001–10 mg/kg) was administered orally (p.o.) 30 min prior to testing, and all of the tested doses reduced the immobility time in the TST without changing the locomotor activity measured in the open field test (OFT). Furthermore, the antidepressant-like effect of OSX (0.01 mg/kg, p.o.) in the TST was prevented by pre-treatment in mice with ketanserin (1 mg/kg, intraperitoneal route (i.p.); a 5-HT2A/2C receptor antagonist), WAY100635 (0.1 mg/kg, subcutaneous (s.c.); a selective 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 selective 5-HT3 receptor antagonist). Taken together, these data demonstrate that OSX has a potent antidepressantlike 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 Published by Elsevier Inc.
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 associated with cognitive decline (Ishrat et al., 2009) and studies have demonstrated 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: [email protected] (L. Savegnago).
http://dx.doi.org/10.1016/j.pnpbp.2015.10.008 0278-5846/© 2015 Published by Elsevier Inc.
populations have shown a higher risk of depression among those with lower selenium intake (Pasco et al., 2012). Conner et al. (2015) suggested 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, heterogeneous, and chronic mental disorder that affects ~120 million people worldwide (Kessler and Bromet, 2013). Furthermore, depressives have impairment of their activities and wellbeing, which leads to incapability 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 patients do not respond to therapy with these drugs (Millan, 2009). Therefore, other treatments should be considered, as they might provide potential effective targets with higher efficacy for the treatment of depression, 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-
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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 seleniumcontaining carbohydrates has been investigated. For example, arylseleno-furanosides and a carbohydrate-derived diselenide demonstrated low toxicity and antioxidant effects (Braga et al., 2010; Vargas et al., 2015). Additionally, selenoglycoside, another series of seleniumcontaining 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 different 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 experiments were performed on separate groups of animals (n = 4–8 animals in each group). The animals were used according to the guidelines 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 University 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 hydrochloride (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.
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 according 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 immediately 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 animals 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 injection, 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 α1adrenoceptor 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 receptor 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 antagonists used in this work were chosen according to previously published data (Martinez et al., 2014; Savegnago et al., 2008). 2.6. Statistical analyses
Fig. 1. Chemical structure of OSX.
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,
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SCH23390, sulpiride, WAY100635, and fluoxetine × OSX treatment) followed by Newman–Keuls test for post hoc comparison when appropriate. A value of P ˂ 0.05 was considered to be significant. 3. Results
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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 significant effect for OSX treatment [F(1,34) = 0.35; P = 0.55], PCPA treatment [F(1,34) = 1.40; P = 0.24] or OSX × PCPA interaction
3.1. Effect of OSX on immobility time in TST and locomotor and exploratory activities in OFT The effect of OSX on immobility time in the TST was statistically significant 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 reduction 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 receptor 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 treatment [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 treatment [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 synthesis, PCPA (Fig. 3D). A two-way ANOVA showed significant differences for OSX treatment [F(1,27) = 57.57, P b 0.0001], and PCPA × OSX treatment interaction [F(1,27) = 6.89, P = 0.014] but not PCPA
Fig. 2. Effect of OSX (0.001–10 mg/kg, p.o.) administered in mice 30 min before on (A) the tail suspension tail (TST), and open field test (B) crossings and (C) rearings. Values were expressed as the mean ± S.E.M. (n = 4–8). (***) P ˂ 0.001 in comparison to the vehicle treated group.
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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.
Table 1 Effect of administration of OSX and antagonists on behavioural parameters in the open field test in mice. Experimental groups
Number of crossings
Number of rearings
Number of animals
Vehicle (saline 0.9%) OSX (0.1 mg/kg) Ketanserin (1 mg/kg) Ketanserin + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) Ondansetron (1 mg/kg) Ondansetron + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) WAY100635 (0.1 mg/kg) WAY100635 + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) PCPA (100 mg/kg) PCPA + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) Prazosin (1 mg/kg) Prazosin + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) Yohimbine (1 mg/kg) Yohimbine + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) SCH233390 (0.05 mg/kg) SCH233390 + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) Sulpiride (50 mg/kg) Sulpiride + OSX
80.63 ± 1.56 70.25 ± 2.56 75.60 ± 6.12 74.33 ± 5.27 92.40 ± 4.13 101.5 ± 11.29 92.80 ± 1.53 95.20 ± 7.72 79.20 ± 10.58 75.20 ± 3.96 83.75 ± 3.70 70.20 ± 4.00 88.40 ± 2.59 84.50 ± 5.90 88.50 ± 4.61 86.00 ± 5.05 84.40 ± 1.20 72.40 ± 6.16 77.80 ± 5.78 78.80 ± 2.59 79.20 ± 10.58 74.00 ± 4.18 74.20 ± 6.53 51.20 ± 5.32 76.60 ± 2.42 78.60 ± 4.29 82.25 ± 3.92 72.20 ± 6.96 64.14 ± 4.67 51.25 ± 7.77 57.60 ± 11.14 57.00 ± 6.26
20.38 ± 1.41 21.88 ± 1.35 18.38 ± 1.75 18.78 ± 2.06 23.25 ± 2.01 21.50 ± 2.90 19.20 ± 2.39 24.60 ± 2.18 19.80 ± 2.87 19.20 ± 2.39 19.20 ± 1.88 25.20 ± 1.68 28.20 ± 4.49 22.20 ± 2.47 28.90 ± 2.79 30.43 ± 5.25 22.00 ± 0.70 17.80 ± 3.86 23.00 ± 2.84 18.80 ± 3.33 19.80 ± 2.87 25.80 ± 2.70 20.00 ± 3.60 17.50 ± 3.12 22.00 ± 0.70 17.80 ± 3.86 19.75 ± 0.94 20.00 ± 2.91 22.86 ± 2.96 23.83 ± 3.73 28.00 ± 4.52 28.17 ± 3.13
8 8 5 8 5 4 5 5 5 5 4 5 8 8 8 7 5 5 5 5 5 5 5 5 5 5 4 5 7 4 5 7
The effect of mice behavioural on the open field test was determined by two-way ANOVA followed by Newman-Keuls test. Data presented are mean values ± S.E.M. (n = 4–8).
[F(1,34) = 1; P = 0.32] on the number of rearings in the open field test was observed (Table 1).
3.3. Involvement of the noradrenergic system on the antidepressant-like effect of OSX Fig. 4A shows that the pre-treatment of mice with prazosin (an α1adrenoceptor antagonist) prevented 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) = 14.78, P = 0.0014] and prazosin × OSX treatment interaction [F(1,16) = 7.35, P = 0.015] but not prazosin treatment [F(1,16) = 0.01, P = 0.92]. No significant effect for OSX treatment [F(1,16) = 1.52, P = 0.23], prazosin treatment [F(1,16) = 0.00, P = 0.98] or OSX × prazosin interaction [F(1,16) = 2.2, P = 0.16] on the number of crossings, and no significant effect for OSX treatment [F(1,16) = 2.03, P = 0.17], prazosin treatment [F(1,29) = 0.12, P = 0.73] or OSX × prazosin interaction [F(1,29) = 0.00, P = 1.00] on the number of rearings in the open-field test was observed (Table 1). Fig. 4B shows that the pre-treatment of mice with yohimbine (an α2-adrenoceptor 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(1,14) = 10.98, P = 0.005], yohimbine × OSX treatment interaction [F(1,14) = 8.28, P = 0.012], but not yohimbine alone [F(1,14) = 3.72, P = 0.074]. The administration of yohimbine alone or in combination with OSX did not affect (P ˃ 0.05) the ambulation in the open-field (Table 1). The two way ANOVA revealed no significant effect of OSX treatment [F(1,16) = 3.97; P = 0.06], yohimbine treatment [F(1,16) = 3.86; P = 0.06] and OSX × yohimbine treatment interaction [F(1,16) = 1.58; P = 0.2] to number of crossings. No significant effect for OSX treatment [F(1,13) = 0.97; P = 0.34], yohimbine treatment [F(1,13) = 3.28; P = 0.09] or OSX × yohimbine interaction
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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 antiimmobility 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 treatment [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 locomotor activity in the open-field test was observed (Table 1). No significant 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 significant 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 interaction [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 interaction [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) =
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Fig. 5. Effect of pretreatment of mice with (A) SCH233390 (0.05 mg/kg, s.c., a dopaminergic 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 presented 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 observed (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 obtained 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-diphenyl3-(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 dopaminergic systems. Regarding the serotoninergic system, there are several lines of evidence reporting that drugs that affect serotonin neurotransmission, such as those inhibiting 5-HT reuptake at nerve terminals or inhibiting monoamines metabolism (MAO inhibitors), are effective in the treatment of depression (Elhwuegi, 2004). In order to investigate 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,
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2013). In this study, the pre-treatment of mice with WAY100635 (a selective 5-HT1A receptor antagonist) abolished OSX antidepressant-like effect, thus demonstrating the 5-HT1A receptor participation in such effect. The involvement of 5-HT2A/C receptor in the antidepressant-like effect 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 ratelimiting enzyme in the biosynthesis of serotonin, tryptophan hydroxylase, 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 noradrenergic 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 antagonist 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 dopaminergic 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 considerable amount of pharmacological evidence regarding the efficacy of antidepressants with dopaminergic effects in the treatment of depression (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 serotonergic, 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 activity 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 regulate the adenylyl cyclase- cAMP signal pathway which needs to be studied. 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 regulating 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 mechanisms 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 depression. Thus, drugs with potential antioxidant action could be attractive 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, consistent 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). However, 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 compound OSX can be considered new and attractive strategy for the management 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).
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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 Grupo de Pesquisa em Neurobiotecnologia — GPN, CDTec, Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil 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 b c
a r t i c l e
i n f o
Article history: Received 11 May 2015 Received in revised form 28 September 2015 Accepted 23 October 2015 Available online 24 October 2015 Keywords: Selenium Antidepressant-like Organoselenium
a b s t r a c t Depression is one of the most commonly diagnosed neuropsychiatric disorders and several studies have demonstrated a role for selenium in mood disorders. For this reason, the present study investigated the role of the monoaminergic system in the antidepressant-like action of (octylseleno)-xylofuranoside (OSX), an organoselenium compound, in the tail suspension test (TST) in mice. For this purpose, OSX (0.001–10 mg/kg) was administered orally (p.o.) 30 min prior to testing, and all of the tested doses reduced the immobility time in the TST without changing the locomotor activity measured in the open field test (OFT). Furthermore, the antidepressant-like effect of OSX (0.01 mg/kg, p.o.) in the TST was prevented by pre-treatment in mice with ketanserin (1 mg/kg, intraperitoneal route (i.p.); a 5-HT2A/2C receptor antagonist), WAY100635 (0.1 mg/kg, subcutaneous (s.c.); a selective 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 selective 5-HT3 receptor antagonist). Taken together, these data demonstrate that OSX has a potent antidepressantlike 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 Published by Elsevier Inc.
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 associated with cognitive decline (Ishrat et al., 2009) and studies have demonstrated 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: [email protected] (L. Savegnago).
http://dx.doi.org/10.1016/j.pnpbp.2015.10.008 0278-5846/© 2015 Published by Elsevier Inc.
populations have shown a higher risk of depression among those with lower selenium intake (Pasco et al., 2012). Conner et al. (2015) suggested 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, heterogeneous, and chronic mental disorder that affects ~120 million people worldwide (Kessler and Bromet, 2013). Furthermore, depressives have impairment of their activities and wellbeing, which leads to incapability 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 patients do not respond to therapy with these drugs (Millan, 2009). Therefore, other treatments should be considered, as they might provide potential effective targets with higher efficacy for the treatment of depression, 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-
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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 seleniumcontaining carbohydrates has been investigated. For example, arylseleno-furanosides and a carbohydrate-derived diselenide demonstrated low toxicity and antioxidant effects (Braga et al., 2010; Vargas et al., 2015). Additionally, selenoglycoside, another series of seleniumcontaining 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 different 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 experiments were performed on separate groups of animals (n = 4–8 animals in each group). The animals were used according to the guidelines 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 University 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 hydrochloride (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.
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 according 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 immediately 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 animals 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 injection, 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 α1adrenoceptor 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 receptor 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 antagonists used in this work were chosen according to previously published data (Martinez et al., 2014; Savegnago et al., 2008). 2.6. Statistical analyses
Fig. 1. Chemical structure of OSX.
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,
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SCH23390, sulpiride, WAY100635, and fluoxetine × OSX treatment) followed by Newman–Keuls test for post hoc comparison when appropriate. A value of P ˂ 0.05 was considered to be significant. 3. Results
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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 significant effect for OSX treatment [F(1,34) = 0.35; P = 0.55], PCPA treatment [F(1,34) = 1.40; P = 0.24] or OSX × PCPA interaction
3.1. Effect of OSX on immobility time in TST and locomotor and exploratory activities in OFT The effect of OSX on immobility time in the TST was statistically significant 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 reduction 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 receptor 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 treatment [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 treatment [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 synthesis, PCPA (Fig. 3D). A two-way ANOVA showed significant differences for OSX treatment [F(1,27) = 57.57, P b 0.0001], and PCPA × OSX treatment interaction [F(1,27) = 6.89, P = 0.014] but not PCPA
Fig. 2. Effect of OSX (0.001–10 mg/kg, p.o.) administered in mice 30 min before on (A) the tail suspension tail (TST), and open field test (B) crossings and (C) rearings. Values were expressed as the mean ± S.E.M. (n = 4–8). (***) P ˂ 0.001 in comparison to the vehicle treated group.
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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.
Table 1 Effect of administration of OSX and antagonists on behavioural parameters in the open field test in mice. Experimental groups
Number of crossings
Number of rearings
Number of animals
Vehicle (saline 0.9%) OSX (0.1 mg/kg) Ketanserin (1 mg/kg) Ketanserin + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) Ondansetron (1 mg/kg) Ondansetron + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) WAY100635 (0.1 mg/kg) WAY100635 + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) PCPA (100 mg/kg) PCPA + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) Prazosin (1 mg/kg) Prazosin + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) Yohimbine (1 mg/kg) Yohimbine + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) SCH233390 (0.05 mg/kg) SCH233390 + OSX Vehicle (saline 0.9%) OSX (0.1 mg/kg) Sulpiride (50 mg/kg) Sulpiride + OSX
80.63 ± 1.56 70.25 ± 2.56 75.60 ± 6.12 74.33 ± 5.27 92.40 ± 4.13 101.5 ± 11.29 92.80 ± 1.53 95.20 ± 7.72 79.20 ± 10.58 75.20 ± 3.96 83.75 ± 3.70 70.20 ± 4.00 88.40 ± 2.59 84.50 ± 5.90 88.50 ± 4.61 86.00 ± 5.05 84.40 ± 1.20 72.40 ± 6.16 77.80 ± 5.78 78.80 ± 2.59 79.20 ± 10.58 74.00 ± 4.18 74.20 ± 6.53 51.20 ± 5.32 76.60 ± 2.42 78.60 ± 4.29 82.25 ± 3.92 72.20 ± 6.96 64.14 ± 4.67 51.25 ± 7.77 57.60 ± 11.14 57.00 ± 6.26
20.38 ± 1.41 21.88 ± 1.35 18.38 ± 1.75 18.78 ± 2.06 23.25 ± 2.01 21.50 ± 2.90 19.20 ± 2.39 24.60 ± 2.18 19.80 ± 2.87 19.20 ± 2.39 19.20 ± 1.88 25.20 ± 1.68 28.20 ± 4.49 22.20 ± 2.47 28.90 ± 2.79 30.43 ± 5.25 22.00 ± 0.70 17.80 ± 3.86 23.00 ± 2.84 18.80 ± 3.33 19.80 ± 2.87 25.80 ± 2.70 20.00 ± 3.60 17.50 ± 3.12 22.00 ± 0.70 17.80 ± 3.86 19.75 ± 0.94 20.00 ± 2.91 22.86 ± 2.96 23.83 ± 3.73 28.00 ± 4.52 28.17 ± 3.13
8 8 5 8 5 4 5 5 5 5 4 5 8 8 8 7 5 5 5 5 5 5 5 5 5 5 4 5 7 4 5 7
The effect of mice behavioural on the open field test was determined by two-way ANOVA followed by Newman-Keuls test. Data presented are mean values ± S.E.M. (n = 4–8).
[F(1,34) = 1; P = 0.32] on the number of rearings in the open field test was observed (Table 1).
3.3. Involvement of the noradrenergic system on the antidepressant-like effect of OSX Fig. 4A shows that the pre-treatment of mice with prazosin (an α1adrenoceptor antagonist) prevented 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) = 14.78, P = 0.0014] and prazosin × OSX treatment interaction [F(1,16) = 7.35, P = 0.015] but not prazosin treatment [F(1,16) = 0.01, P = 0.92]. No significant effect for OSX treatment [F(1,16) = 1.52, P = 0.23], prazosin treatment [F(1,16) = 0.00, P = 0.98] or OSX × prazosin interaction [F(1,16) = 2.2, P = 0.16] on the number of crossings, and no significant effect for OSX treatment [F(1,16) = 2.03, P = 0.17], prazosin treatment [F(1,29) = 0.12, P = 0.73] or OSX × prazosin interaction [F(1,29) = 0.00, P = 1.00] on the number of rearings in the open-field test was observed (Table 1). Fig. 4B shows that the pre-treatment of mice with yohimbine (an α2-adrenoceptor 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(1,14) = 10.98, P = 0.005], yohimbine × OSX treatment interaction [F(1,14) = 8.28, P = 0.012], but not yohimbine alone [F(1,14) = 3.72, P = 0.074]. The administration of yohimbine alone or in combination with OSX did not affect (P ˃ 0.05) the ambulation in the open-field (Table 1). The two way ANOVA revealed no significant effect of OSX treatment [F(1,16) = 3.97; P = 0.06], yohimbine treatment [F(1,16) = 3.86; P = 0.06] and OSX × yohimbine treatment interaction [F(1,16) = 1.58; P = 0.2] to number of crossings. No significant effect for OSX treatment [F(1,13) = 0.97; P = 0.34], yohimbine treatment [F(1,13) = 3.28; P = 0.09] or OSX × yohimbine interaction
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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 antiimmobility 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 treatment [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 locomotor activity in the open-field test was observed (Table 1). No significant 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 significant 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 interaction [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 interaction [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) =
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Fig. 5. Effect of pretreatment of mice with (A) SCH233390 (0.05 mg/kg, s.c., a dopaminergic 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 presented 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 observed (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 obtained 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-diphenyl3-(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 dopaminergic systems. Regarding the serotoninergic system, there are several lines of evidence reporting that drugs that affect serotonin neurotransmission, such as those inhibiting 5-HT reuptake at nerve terminals or inhibiting monoamines metabolism (MAO inhibitors), are effective in the treatment of depression (Elhwuegi, 2004). In order to investigate 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,
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2013). In this study, the pre-treatment of mice with WAY100635 (a selective 5-HT1A receptor antagonist) abolished OSX antidepressant-like effect, thus demonstrating the 5-HT1A receptor participation in such effect. The involvement of 5-HT2A/C receptor in the antidepressant-like effect 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 ratelimiting enzyme in the biosynthesis of serotonin, tryptophan hydroxylase, 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 noradrenergic 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 antagonist 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 dopaminergic 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 considerable amount of pharmacological evidence regarding the efficacy of antidepressants with dopaminergic effects in the treatment of depression (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 serotonergic, 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 activity 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 regulate the adenylyl cyclase- cAMP signal pathway which needs to be studied. 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 regulating 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 mechanisms 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 depression. Thus, drugs with potential antioxidant action could be attractive 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, consistent 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). However, 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 compound OSX can be considered new and attractive strategy for the management 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).
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