Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Antidepressant effects of valproic acid in an animal model of depression

Antidepressant effects of valproic acid in an animal model of depression Valproic acid, beside its anticonvulsant action, is widely used as a mood stabilizer in the therapy of bipolar disorder. The potential antidepressant action of valproic acid has not been sufficiently characterized so far. The aim of the present study was to evaluate the antidepressant effect of valproic acid in an aldosterone model of depression. Subchronic treatment with valproic acid resulted in a reduction of the time spent in immobility in the forced swim test. In conclusion, the present study provides evidence on antidepressant effects of valproic acid using a classical behavioral approach for testing the efficacy of antidepressant drug in animal models. Keywords sodium valproate – forced swimming test – antidepressant effect INTRODUCTION Valproic acid is an antiepileptic drug used in the clinical Division of the State Veterinary and Food Administration of practice for a long time. Beside its anticonvulsant action, the Slovak Republic. Animals were divided into four groups it is widely used as a mood stabilizer in the therapy of (n = 9–10 per group) based on the treatment administered. bipolar disorder. Together with other thymoprofylactics Aldosterone (d-aldosterone, Sigma, USA) or vehicle was and anticonvulsants, such as tiagabine, it also exhibits continuously administered via subcutaneous osmotic antidepressant effect (Pistovcakova et. al 2008). The exact minipumps for 14 days (Model 2002, Alzet, Alza Corp., USA). mechanism of antidepressant action is still unknown, and The dose of aldosterone was chosen based on our previous therefore, it is tested in various animal models of depression studies (Hlavacova & Jezova, 2008; Hlavacova et al. 2012). (Lima et al. 2017, Qiu et. al 2015). However, the data from the Simultaneously, valproic acid was administered in drinking literature are still insufficient to fully elucidate the potential water at a dose of 100 mg/1 kg body weight/day continuously antidepressant action of valproic acid. for 14 days. Animals from placebo groups received drinking The aim of the present study was to evaluate the water without valproic acid. antidepressant effect of valproic acid in an animal model of On day 14 of the treatments, rats from each group were depression based on elevated circulating concentrations of subjected to behavioral testing in the forced swim test to aldosterone, which was shown to induce increased anxiety evaluate depression-like behavior. Behavioral tests were and depression-like behaviors (Hlavacova & Jezova, 2008; conducted during the light phase of the day, between 9.00 and Hlavacova et al. 2012). 11.00 h. The rats were individually placed in a glass cylindrical tank filled with tap water (23±1°C). The testing session lasted MATERIAL AND METHODS 15 min and was videotaped by camera positioned in front of the tank. Rats behavior was scored for the last 5 min of the 15 Forty male adult Sprague-Dawley rats were used. Animals min session (Hlavacova et al. 2012). The percentage of time were housed individually in standard cages with free which the animal spent immobile was rated as depression- access to rat chow and water. All experimental procedures like behavior (Hlavacova et al. 2018). In addition, time which were approved by the Animal Health and Animal Welfare animal spent struggling and swimming was also measured. * E-mail: katarina.buzgoova@savba.sk © European Pharmaceutical Journal OR 1 Eur. Pharm. J. 2019, 66(2), 1-3. Antidepressant eects of v ff alproic acid in an animal model of depression Buzgoova K. et al. Figure 1. Time spent in immobility in forced swimming test in rats simultaneously treated with valproic acid and aldosterone. The results are expressed as means ± SEM. Overall level of significance was defined as p<0.05. RESULTS depression. On the other hand, the same dose of valproic acid The data were checked for the normality of distribution injected intraperitoneally to mice increased the immobility using the Shapiro–Wilk test and were analyzed by two-way in the forced swim test, indicating its depressogenic effects analysis of variance (ANOVA) for factors valproic acid (valproic (Lima et al. 2017). That study revealed antidepressant effects acid and placebo groups) and aldosterone (aldosterone and of lower dose of valproic acid, namely, 30 and 100 mg/ vehicle groups). kg. The dose of valproic acid selected in the present study Statistical analysis of data obtained from the forced swim test was observed to be effective in the inhibition of histone showed a significant main effect of valproic acid treatment deacetylase (Bredy and Barad, 2008; Heinrichs et al. 2013) (F(1,34) = 5.05, p < 0.05) on immobility time. Valproic- and changes in epigenetic mechanisms have been associated acid-treated rats spent significantly shorter time immobile with the pathophysiology of depression. compared to rats treated with placebo (Fig. 1). The animals Unlike our previous results (Hlavacova et al. 2012), the time treated with aldosterone spent longer time in immobility, spent in immobility only tended to be higher in aldosterone- but the difference did not reach significance. No significant treated rats. One reason for this discrepancy could be the use main effects of valproic acid and aldosterone treatments or of Sprague-Dawley and not Wistar strain of rats in the present their interaction were observed in struggling and swimming experiments. Another cause of the difference could be the behaviors (data not shown). cessation of the production of the aldosterone substance used previously by the chemical company and the need to DISCUSSION purchase aldosterone from another company. In conclusion, the present study provides evidence on The present findings show antidepressant effect of sub- antidepressant effects of valproic acid using a classical chronic treatment with valproic acid in aldosterone model behavioral approach for testing the efficacy of antidepressant of depression. The valproic acid is clinically used in the drug in animal models. It may be related to the epigenetic treatment of bipolar disorder and there are signals of its modulations induced by the same dose of valproic acid efficacy in bipolar depression (Smith et al. 2010). However, described recently (Buzgoova et al. 2019). the exact experimental evidence of antidepressant effects of ACKNOWLEDGMENTS valproic acid is limited and contradictory. The dose of valproic acid used in the present study was 100 mg/kg/day. The research group of Qiu and colleagues (2014; The study was supported by the grant of Slovak Research and 2015) reported antidepressant-like effects of valproic acid Development Agency under the contract No. APVV-15-0388 treatment via intragastric gavage at a dose of 300 mg/kg/ and VEGA 2/0042/19. day in rats exposed to chronic unpredictable stress model of 2 3 Eur. Pharm. J. 2019, 66(2), 1-3. Antidepressant eects of v ff alproic acid in an animal model of depression Buzgoova K. et al. References [1] Bredy TW, Barad M. The histone deacetylase inhibitor valproic [7] Pistovcakova J, Dostalek M, Sulcova A, Jezova D. Tiagabine acid enhances acquisition, extinction, and reconsolidation of treatment is associated with neurochemical, immune and conditioned fear. Learn Mem. 2008; 15(1):39-45. behavioural alterations in the olfactory bulbectomized rat model [2] Heinrichs SC, Leite-Morris KA, Rasmusson AM, Kaplan GB. of depression. Pharmacopsychiatry. 2008; 41(2):54-9. Repeated valproate treatment facilitates fear extinction under [8] Qiu HM, Yang JX, Jiang XH, Hu XY, Liu D, Zhou QX. Enhancing specific stimulus conditions. Neurosci Lett. 2013; 552:108-13. tyrosine hydroxylase and tryptophan hydroxylase expression and [3] Hlavacova N, Jezova D. Chronic treatment with the improving oxidative stress involved in the antidepressant effect mineralocorticoid hormone aldosterone results in increased of sodium valproate on rats undergoing chronic unpredicted anxiety-like behavior. Horm Behav. 2008; 54(1):90-7. stress. Neuroreport. 2015; 26(18):1145-50. [4] Hlavacova N, Li Y, Pehrson A, Sanchez C, Bermudez I, Csanova [9] Qiu HM, Yang JX, Liu D, Fei HZ, Hu XY, Zhou QX. Antidepressive A, Jezova D, Franklin M. Effects of vortioxetine on biomarkers effect of sodium valproate involving suppression of corticotropin- associated with glutamatergic activity in an SSRI insensitive releasing factor expression and elevation of BDNF expression in model of depression in female rats. Prog Neuropsychopharmacol rats exposed to chronic unpredicted stress. Neuroreport. 2014; Biol Psychiatry. 2018; 82:332-338. 25(4):205-10. [5] Hlavacova N, Wes PD, Ondrejcakova M, Flynn ME, Poundstone [10] Smith LA, Cornelius VR, Azorin JM, Perugi G, Vieta E, Young PK, Babic S, Murck H, Jezova D. Subchronic treatment with AH, Bowden CL. Valproate for the treatment of acute bipolar aldosterone induces depression-like behaviours and gene depression: systematic review and meta-analysis. J Aec ff t Disord. expression changes relevant to major depressive disorder. Int J 2010; 122(1-2):1-9. Neuropsychopharmacol. 2012;15(2):247-65. [11] Buzgoova K, Graban J, Balagova L, Hlavacova N, Jezova D. Brain [6] Lima IVA, Almeida-Santos AF, Ferreira-Vieira TH, Aguiar DC, derived neurotrophic factor expression and DNA methylation Ribeiro FM, Campos AC, de Oliveira ACP. Antidepressant-like in response to subchronic valproic acid and/or aldosterone effect of valproic acid-Possible involvement of PI3K/Akt mTOR treatment. Croat Med J. 2019 (in press). pathway. Behav Brain Res. 2017; 329:166-171. 2 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Facultatis Pharmaceuticae Universitatis Comenianae de Gruyter

Antidepressant effects of valproic acid in an animal model of depression

Loading next page...
 
/lp/de-gruyter/antidepressant-effects-of-valproic-acid-in-an-animal-model-of-9vyCxPDTOE
Publisher
de Gruyter
Copyright
© 2019 K. Buzgoova et al., published by Sciendo
ISSN
1338-6786
eISSN
2453-6725
DOI
10.2478/afpuc-2019-0006
Publisher site
See Article on Publisher Site

Abstract

Valproic acid, beside its anticonvulsant action, is widely used as a mood stabilizer in the therapy of bipolar disorder. The potential antidepressant action of valproic acid has not been sufficiently characterized so far. The aim of the present study was to evaluate the antidepressant effect of valproic acid in an aldosterone model of depression. Subchronic treatment with valproic acid resulted in a reduction of the time spent in immobility in the forced swim test. In conclusion, the present study provides evidence on antidepressant effects of valproic acid using a classical behavioral approach for testing the efficacy of antidepressant drug in animal models. Keywords sodium valproate – forced swimming test – antidepressant effect INTRODUCTION Valproic acid is an antiepileptic drug used in the clinical Division of the State Veterinary and Food Administration of practice for a long time. Beside its anticonvulsant action, the Slovak Republic. Animals were divided into four groups it is widely used as a mood stabilizer in the therapy of (n = 9–10 per group) based on the treatment administered. bipolar disorder. Together with other thymoprofylactics Aldosterone (d-aldosterone, Sigma, USA) or vehicle was and anticonvulsants, such as tiagabine, it also exhibits continuously administered via subcutaneous osmotic antidepressant effect (Pistovcakova et. al 2008). The exact minipumps for 14 days (Model 2002, Alzet, Alza Corp., USA). mechanism of antidepressant action is still unknown, and The dose of aldosterone was chosen based on our previous therefore, it is tested in various animal models of depression studies (Hlavacova & Jezova, 2008; Hlavacova et al. 2012). (Lima et al. 2017, Qiu et. al 2015). However, the data from the Simultaneously, valproic acid was administered in drinking literature are still insufficient to fully elucidate the potential water at a dose of 100 mg/1 kg body weight/day continuously antidepressant action of valproic acid. for 14 days. Animals from placebo groups received drinking The aim of the present study was to evaluate the water without valproic acid. antidepressant effect of valproic acid in an animal model of On day 14 of the treatments, rats from each group were depression based on elevated circulating concentrations of subjected to behavioral testing in the forced swim test to aldosterone, which was shown to induce increased anxiety evaluate depression-like behavior. Behavioral tests were and depression-like behaviors (Hlavacova & Jezova, 2008; conducted during the light phase of the day, between 9.00 and Hlavacova et al. 2012). 11.00 h. The rats were individually placed in a glass cylindrical tank filled with tap water (23±1°C). The testing session lasted MATERIAL AND METHODS 15 min and was videotaped by camera positioned in front of the tank. Rats behavior was scored for the last 5 min of the 15 Forty male adult Sprague-Dawley rats were used. Animals min session (Hlavacova et al. 2012). The percentage of time were housed individually in standard cages with free which the animal spent immobile was rated as depression- access to rat chow and water. All experimental procedures like behavior (Hlavacova et al. 2018). In addition, time which were approved by the Animal Health and Animal Welfare animal spent struggling and swimming was also measured. * E-mail: katarina.buzgoova@savba.sk © European Pharmaceutical Journal OR 1 Eur. Pharm. J. 2019, 66(2), 1-3. Antidepressant eects of v ff alproic acid in an animal model of depression Buzgoova K. et al. Figure 1. Time spent in immobility in forced swimming test in rats simultaneously treated with valproic acid and aldosterone. The results are expressed as means ± SEM. Overall level of significance was defined as p<0.05. RESULTS depression. On the other hand, the same dose of valproic acid The data were checked for the normality of distribution injected intraperitoneally to mice increased the immobility using the Shapiro–Wilk test and were analyzed by two-way in the forced swim test, indicating its depressogenic effects analysis of variance (ANOVA) for factors valproic acid (valproic (Lima et al. 2017). That study revealed antidepressant effects acid and placebo groups) and aldosterone (aldosterone and of lower dose of valproic acid, namely, 30 and 100 mg/ vehicle groups). kg. The dose of valproic acid selected in the present study Statistical analysis of data obtained from the forced swim test was observed to be effective in the inhibition of histone showed a significant main effect of valproic acid treatment deacetylase (Bredy and Barad, 2008; Heinrichs et al. 2013) (F(1,34) = 5.05, p < 0.05) on immobility time. Valproic- and changes in epigenetic mechanisms have been associated acid-treated rats spent significantly shorter time immobile with the pathophysiology of depression. compared to rats treated with placebo (Fig. 1). The animals Unlike our previous results (Hlavacova et al. 2012), the time treated with aldosterone spent longer time in immobility, spent in immobility only tended to be higher in aldosterone- but the difference did not reach significance. No significant treated rats. One reason for this discrepancy could be the use main effects of valproic acid and aldosterone treatments or of Sprague-Dawley and not Wistar strain of rats in the present their interaction were observed in struggling and swimming experiments. Another cause of the difference could be the behaviors (data not shown). cessation of the production of the aldosterone substance used previously by the chemical company and the need to DISCUSSION purchase aldosterone from another company. In conclusion, the present study provides evidence on The present findings show antidepressant effect of sub- antidepressant effects of valproic acid using a classical chronic treatment with valproic acid in aldosterone model behavioral approach for testing the efficacy of antidepressant of depression. The valproic acid is clinically used in the drug in animal models. It may be related to the epigenetic treatment of bipolar disorder and there are signals of its modulations induced by the same dose of valproic acid efficacy in bipolar depression (Smith et al. 2010). However, described recently (Buzgoova et al. 2019). the exact experimental evidence of antidepressant effects of ACKNOWLEDGMENTS valproic acid is limited and contradictory. The dose of valproic acid used in the present study was 100 mg/kg/day. The research group of Qiu and colleagues (2014; The study was supported by the grant of Slovak Research and 2015) reported antidepressant-like effects of valproic acid Development Agency under the contract No. APVV-15-0388 treatment via intragastric gavage at a dose of 300 mg/kg/ and VEGA 2/0042/19. day in rats exposed to chronic unpredictable stress model of 2 3 Eur. Pharm. J. 2019, 66(2), 1-3. Antidepressant eects of v ff alproic acid in an animal model of depression Buzgoova K. et al. References [1] Bredy TW, Barad M. The histone deacetylase inhibitor valproic [7] Pistovcakova J, Dostalek M, Sulcova A, Jezova D. Tiagabine acid enhances acquisition, extinction, and reconsolidation of treatment is associated with neurochemical, immune and conditioned fear. Learn Mem. 2008; 15(1):39-45. behavioural alterations in the olfactory bulbectomized rat model [2] Heinrichs SC, Leite-Morris KA, Rasmusson AM, Kaplan GB. of depression. Pharmacopsychiatry. 2008; 41(2):54-9. Repeated valproate treatment facilitates fear extinction under [8] Qiu HM, Yang JX, Jiang XH, Hu XY, Liu D, Zhou QX. Enhancing specific stimulus conditions. Neurosci Lett. 2013; 552:108-13. tyrosine hydroxylase and tryptophan hydroxylase expression and [3] Hlavacova N, Jezova D. Chronic treatment with the improving oxidative stress involved in the antidepressant effect mineralocorticoid hormone aldosterone results in increased of sodium valproate on rats undergoing chronic unpredicted anxiety-like behavior. Horm Behav. 2008; 54(1):90-7. stress. Neuroreport. 2015; 26(18):1145-50. [4] Hlavacova N, Li Y, Pehrson A, Sanchez C, Bermudez I, Csanova [9] Qiu HM, Yang JX, Liu D, Fei HZ, Hu XY, Zhou QX. Antidepressive A, Jezova D, Franklin M. Effects of vortioxetine on biomarkers effect of sodium valproate involving suppression of corticotropin- associated with glutamatergic activity in an SSRI insensitive releasing factor expression and elevation of BDNF expression in model of depression in female rats. Prog Neuropsychopharmacol rats exposed to chronic unpredicted stress. Neuroreport. 2014; Biol Psychiatry. 2018; 82:332-338. 25(4):205-10. [5] Hlavacova N, Wes PD, Ondrejcakova M, Flynn ME, Poundstone [10] Smith LA, Cornelius VR, Azorin JM, Perugi G, Vieta E, Young PK, Babic S, Murck H, Jezova D. Subchronic treatment with AH, Bowden CL. Valproate for the treatment of acute bipolar aldosterone induces depression-like behaviours and gene depression: systematic review and meta-analysis. J Aec ff t Disord. expression changes relevant to major depressive disorder. Int J 2010; 122(1-2):1-9. Neuropsychopharmacol. 2012;15(2):247-65. [11] Buzgoova K, Graban J, Balagova L, Hlavacova N, Jezova D. Brain [6] Lima IVA, Almeida-Santos AF, Ferreira-Vieira TH, Aguiar DC, derived neurotrophic factor expression and DNA methylation Ribeiro FM, Campos AC, de Oliveira ACP. Antidepressant-like in response to subchronic valproic acid and/or aldosterone effect of valproic acid-Possible involvement of PI3K/Akt mTOR treatment. Croat Med J. 2019 (in press). pathway. Behav Brain Res. 2017; 329:166-171. 2 3

Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianaede Gruyter

Published: Nov 1, 2019

Keywords: sodium valproate; forced swimming test; antidepressant effect

References