Imipramine Can Be Effective on Depressive-Like Behaviors, but Not on Neurotrophic Factor Levels in an Animal Model for Bipolar Disorder Induced by Ouabain.

INTRODUCTION: Despite possible risks of mania switching with the long-term use of antidepressants in patients with bipolar disorder (BD), these drugs may help in depressive episodes. Alterations in neurotrophic factor levels seem to be involved in the pathophysiology of BD. The present study aimed to evaluate the effect of acute treatment of imipramine on behavior and neurotrophic levels in rats submitted to the animal model for BD induced by ouabain. METHODS: Wistar rats received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid or ouabain (10-3 M). Following the ICV administration, the rats were treated for 14 days with saline (NaCl 0.9%, i.p.), lithium (47.5 mg/kg, i.p.), or valproate (200 mg/kg, i.p.). On the 13th and 14th days of treatment, the animals received an additional injection of saline or imipramine (10 mg/kg, i.p.). Behavior tests were evaluated 7 and 14 days after ICV injection. Adrenal gland weight and concentrations of ACTH were evaluated. Levels of neurotrophins BDNF, NGF, NT-3, and GDNF were measured in the frontal cortex and hippocampus by ELISA test. RESULTS: The administration of ouabain induced mania- and depressive-like behavior in the animals 7 and 14 days after ICV, respectively. The treatment with lithium and valproate reversed the mania-like behavior. All treatments were able to reverse most of the depressive-like behaviors induced by ouabain. Moreover, ouabain increased HPA-axis parameters in serum and decreased the neurotrophin levels in the frontal cortex and hippocampus. All treatments, except imipramine, reversed these alterations. CONCLUSION: It can be suggested that acute administration of imipramine alone can be effective on depressive-like symptoms but not on neurotrophic factor alterations present in BD.

Ouabain induces memory impairment and alter the BDNF signaling pathway in an animal model of bipolar disorder: Cognitive and neurochemical alterations in BD model.

BACKGROUND: The present study aims to evaluate the effects of ouabain on memory and neurotrophic parameters in the brains of rats. METHODS: Wistar rats received an intracerebroventricular (ICV) injection of ouabain or artificial cerebrospinal fluid (aCSF). Seven and 14 days after ICV administration, the animals were subjected to the open-field and splash tests. Furthermore, the pro-BDNF, BDNF, TrkB, and CREB were assessed in the frontal cortex and hippocampus of the rats, in both seven and 14 days after ICV injection. The memory of the animals was tested by novel object recognition test (NOR) and inhibitory avoidance task (IA), only 14 days after ICV administration. RESULTS: Ouabain increased locomotion and exploration in the animals seven days after its administration; however, 14 days after ICV, these behavioral parameters return to the basal level. Seven days after ouabain administration increased grooming behavior in the splash test; on the other hand, seven days after ouabain injection decreased the grooming behavior, which is considered an anhedonic response. Besides, ouabain decreased recognition index in the NOR and decreased aversive memory in the IA, when compared to the control group. The levels of pro-BDNF and BDNF decreased in the frontal cortex seven days after ouabain; but its receptor (TrkB) and CREB decreased seven and 14 days after ouabain, in both cerebral structures evaluated. CONCLUSION: Ouabain-induced animal model of BD is an excellent model to assess memory alteration, observed in bipolar patients. Besides, the memory impairment induced by ouabain seems to be related to BDNF signaling pathway alterations.

Role of epigenetic regulatory enzymes in animal models of mania induced by amphetamine and paradoxical sleep deprivation.

It is known that bipolar disorder has a multifactorial aetiology where the interaction between genetic and environmental factors is responsible for its development. Because of this, epigenetics has been largely studied in psychiatric disorders. The present study aims to evaluate the effects of histone deacetylase inhibitors on epigenetic enzyme alterations in rats or mice submitted to animal models of mania induced by dextro-amphetamine or sleep deprivation, respectively. Adult male Wistar rats were subjected to 14 days of dextro-amphetamine administration, and from the eighth to the fourteenth day, the animals were treated with valproate and sodium butyrate in addition to dextro-amphetamine injections. Adult C57BL/6 mice received 7 days of valproate or sodium butyrate administration, being sleep deprived at the last 36 hr of the protocol. Locomotor and exploratory activities of rats and mice were evaluated in the open-field test, and histone deacetylase, DNA methyltransferase, and histone acetyltransferase activities were assessed in the frontal cortex, hippocampus, and striatum. Dextro-amphetamine and sleep deprivation induced hyperactivity and increased histone deacetylase and DNA methyltransferase activities in the animal's brain. Valproate and sodium butyrate were able to reverse hyperlocomotion induced by both animal models, as well as the alterations on histone deacetylase and DNA methyltransferase activities. There was a positive correlation between enzyme activities and number of crossings for both models. Histone deacetylase and DNA methyltransferase activities also presented a positive correlation between theirselves. These results suggest that epigenetics can play an important role in BD pathophysiology as well as in its treatment.

HDAC inhibitors reverse mania-like behavior and modulate epigenetic regulatory enzymes in an animal model of mania induced by Ouabain.

BACKGROUND: The etiology of bipolar disorder (BD) is multifactorial, involving both environmental and genetic factors. Current pharmacological treatment is associated with several side effects, which are the main reason patients discontinue treatment. Epigenetic alterations have been studied for their role in the pathophysiology of BD, as they bridge the gap between gene and environment. OBJECTIVE: Evaluate the effects of histone deacetylase inhibitors on behavior and epigenetic enzymes activity in a rat model of mania induced by ouabain. METHODS: Adult male rats were subjected to a single intracerebroventricular injection of ouabain (10-3 M) followed by 7 days of valproate (200 mg/kg) or sodium butyrate (600 mg/kg) administration. Locomotor and exploratory activities were evaluated in the open-field test. Histone deacetylase, DNA methyltransferase, and histone acetyltransferase activity were assessed in the frontal cortex, hippocampus, and striatum. RESULTS: Ouabain induced hyperactivity in rats, which was reversed by valproate and sodium butyrate treatment. Ouabain did not alter the activity of any of the enzymes evaluated. However, valproate and sodium butyrate decreased the activity of histone deacetylase and DNA methyltransferase. Moreover, there was a positive correlation between these two enzymes. CONCLUSION: These results suggest that targeting epigenetic mechanisms may play an important role in mania-like behavior management.

Effects of lithium and valproate on behavioral parameters and neurotrophic factor levels in an animal model of mania induced by paradoxical sleep deprivation.

The present study aimed to evaluate the effects of treatment with lithium (Li) and valproate (VPA) on behaviors and brain BDNF, NGF, NT-3, NT-4 and GDNF levels in mice submitted to paradoxical sleep deprivation (PSD), which induces an animal model of mania. Male C57BL/6J mice received an intraperitoneal (i.p.) injection of saline solution (NaCl 0.09%, 1 ml/kg), Li (47.3 mg/kg, 1 ml/kg) or VPA (200 mg/kg, 1 ml/kg) once a day for seven days. Animals were randomly distributed into six groups (n = 10 per group): (1) Control + Sal; (2) Control + Li; (3) Control + VPA; (4) PSD + Sal; (5) PSD + Li; or (6) PSD + VPA. Animals were submitted to 36 h of PSD, and then, they were submitted to the open field test. The frontal cortex and hippocampus were dissected from the brain. The manic-like behaviors in the mice were analyzed. Treatment with Li and VPA reversed the behavioral alterations induced by PSD. PSD decreased BDNF, NGF, and GDNF levels in the frontal cortex and hippocampus of mice. The administration of Li and VPA protected the brain against the damage induced by PSD. However, PSD and the administration of Li and VPA did not affect the levels of NT-3 and NT-4 in either brain structure evaluated. In conclusion, the PSD protocol induced manic-like behavior in rats and induced alterations in neurotrophic factor levels. It seems that neurotrophic factors and sleep are essential targets to treat BD.

Validation of the animal model of bipolar disorder induced by Ouabain: face, construct and predictive perspectives.

A particular challenge in the development of a bipolar disorder (BD) model in animals is the complicated clinical course of the condition, characterized by manic, depressive and mixed mood episodes. Ouabain (OUA) is an inhibitor of Na+/K+-ATPase enzyme. Intracerebroventricular (ICV) injection of this drug in rats has been regarded a proper model to study BD by mimic specific manic symptoms, which are reversed by lithium (Li), an important mood stabilizer drug. However, further validation of this experimental approach is required to characterize it as an animal model of BD, including depressive-like behaviors. The present study aimed to assess manic- and depressive-like behaviors, potential alteration in the hypothalamic-pituitary-adrenal (HPA) system and oxidative stress parameters after a single OUA ICV administration in adult male Wistar rats. Moreover, we evaluated Li effects in this experimental setting. Data show that OUA ICV administration could constitute a suitable model for BD since the injection of the drug triggered manic- and depressive-like behaviors in the same animal. Additionally, the OUA model mimics significant physiological and neurochemical alterations detected in BD patients, including an increase in oxidative stress and change in HPA axis. Our findings suggest that decreased Na+/K+-ATPase activity detected in bipolar patients may be linked to increased secretion of glucocorticoid hormones and oxidative damage, leading to the marked behavioral swings. The Li administration mitigated these pathological changes in the rats. The proposed OUA model is regarded as suitable to simulate BD by complying with all validities required to a proper animal model of the psychiatric disorder.

Tamoxifen has an anti-manic effect but not protect the brain against oxidative stress in an animal model of mania induced by ouabain.

Studies have suggested the involvement of oxidative stress in the physiopathology of bipolar disorder. Preclinical data have shown that PKC inhibitors may act as mood-stabilizing agents and protect the brain in animal models of mania. The present study aimed to evaluate the effects of Lithium (Li) or tamoxifen (TMX) on behavioral changes and oxidative stress parameters in an animal model of mania induced by ouabain (OUA). Wistar rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (ACSF). From the day following ICV injection, the rats were treated for seven days with intraperitoneal injections of saline, Li or TMX twice a day. On the 7th day after OUA injection, locomotor activity was measured using the open-field test, and the oxidative stress parameters were evaluated in the hippocampus and frontal cortex of rats. The results showed that OUA induced hyperactivity in rats, which is considered a manic-like behavior. Also, OUA increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of rats. The Li or TMX treatment reversed the manic-like behavior induced by OUA. Besides, Li, but not TMX, reversed the oxidative damage caused by OUA. These results suggest that the manic-like effects induced by OUA and the antimanic effects of TMX seem not to be related to the oxidative stress.

Inhibition of GSK-3ß on Behavioral Changes and Oxidative Stress in an Animal Model of Mania.

The present study evaluated the effects of AR-A014418 on behavioral and oxidative stress parameters of rats submitted to the animal model of mania induced by ouabain (OUA). Wistar rats were submitted to stereotaxic surgery and received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid (aCSF), OUA, or AR-A014418. After 7 days, the animals were submitted to open-field test. After behavioral analysis, the brains were dissected in frontal cortex and hippocampus to the evaluation of oxidative stress. The OUA induced manic-like behavior in rats, which was reversed by AR-A014418 treatment. The ICV administration of OUA increases the levels of superoxide in submitochondrial particles, lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane, protein carbonyl, 3-nitrotyrosine, and activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GR) in both structures evaluated. In general, the treatment with AR-A014418 reversed these effects of OUA on the submitochondrial particles, LPH, 4-HNE, 8-isoprostane, protein carbonyl, 3-nitrotyrosine levels, and SOD activity. Furthermore, the injection of OUA decreased the catalase activity, and AR-A014418 promoted an increase in activity of this enzyme in the brain structures. These results suggest that GSK-3ß inhibition can modulate manic-like behaviors. Also, it can be suggested that inhibition of GSK-3ß can be effective against oxidative stress. However, more studies are needed to better elucidate these mechanisms. Graphical Abstract The effects of AR-A014418 on the behavioral and oxidative stress parameters in the animal model of mania induced by ouabain. Superoxide = superoxide production in submitochondrial particles; LPH = lipid hydroperoxide; 4-HNE = 4-hydroxynonenal; SOD = superoxide dismutase; GPx = glutathione peroxidase; GR = glutathione reductase.

Hypericum perforatum chronic treatment affects cognitive parameters and brain neurotrophic factor levels

Objective: To evaluate the effects of Hypericum perforatum (hypericum) on cognitive behavior and neurotrophic factor levels in the brain of male and female rats. Methods: Male and female Wistar rats were treated with hypericum or water during 28 days by gavage. The animals were then subjected to the open-field test, novel object recognition and step-down inhibitory avoidance test. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-line derived neurotrophic factor (GDNF) levels were evaluated in the hippocampus and frontal cortex. Results: Hypericum impaired the acquisition of short- and long-term aversive memory in male rats, evaluated in the inhibitory avoidance test. Female rats had no immediate memory acquisition and decreased short-term memory acquisition in the inhibitory avoidance test. Hypericum also decreased the recognition index of male rats in the object recognition test. Female rats did not recognize the new object in either the short-term or the long-term memory tasks. Hypericum decreased BDNF in the hippocampus of male and female rats. Hypericum also decreased NGF in the hippocampus of female rats. Conclusions: The long-term administration of hypericum appears to cause significant cognitive impairment in rats, possibly through a reduction in the levels of neurotrophic factors. This effect was more expressive in females than in males.

Hypericum perforatum chronic treatment affects cognitive parameters and brain neurotrophic factor levels.

OBJECTIVE: To evaluate the effects of Hypericum perforatum (hypericum) on cognitive behavior and neurotrophic factor levels in the brain of male and female rats. METHODS: Male and female Wistar rats were treated with hypericum or water during 28 days by gavage. The animals were then subjected to the open-field test, novel object recognition and step-down inhibitory avoidance test. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-line derived neurotrophic factor (GDNF) levels were evaluated in the hippocampus and frontal cortex. RESULTS: Hypericum impaired the acquisition of short- and long-term aversive memory in male rats, evaluated in the inhibitory avoidance test. Female rats had no immediate memory acquisition and decreased short-term memory acquisition in the inhibitory avoidance test. Hypericum also decreased the recognition index of male rats in the object recognition test. Female rats did not recognize the new object in either the short-term or the long-term memory tasks. Hypericum decreased BDNF in the hippocampus of male and female rats. Hypericum also decreased NGF in the hippocampus of female rats. CONCLUSIONS: The long-term administration of hypericum appears to cause significant cognitive impairment in rats, possibly through a reduction in the levels of neurotrophic factors. This effect was more expressive in females than in males.

Resilience Dysregulation in Major Depressive Disorder: Focus on Glutamatergic Imbalance and Microglial Activation.

BACKGROUND: Many studies have been shown an important role of glutamatergic system as well microglial activation in the pathophysiology of major depressive disorder (MDD). In humans most resistant to the development of psychiatric disorders, including MDD, are observed a greater degree of resilience resulting from stress. Less resilience is associated with neuroendocrine and neuroinflammatory markers, as well as with glutamatergic system dysregulation. Thus, this review we highlighted findings from literature identifying the function of glutamatergic system, microglial activation and inflammation in resilience. METHODS: We conducted a review of computerized databases from 1970 to 2017. RESULTS: There is an association between microglial activation and glutamatergic system activation with stress vulnerability and resilience. CONCLUSIONS: Glutamate neurotransmission, including neurotransmitter synthesis, signalling, and glutamate receptor functions and expression all seem to be involved with both stress vulnerability and resilience. Moreover, inflammation and microglial activation mediate individual differences in resilience and the risk of stress-induced MDD.

The Effects of Histone Deacetylase Inhibition on the Levels of Cerebral Cytokines in an Animal Model of Mania Induced by Dextroamphetamine.

Studies have suggested the involvement of inflammatory processes in the physiopathology of bipolar disorder. Preclinical evidences have shown that histone deacetylase inhibitors may act as mood-stabilizing agents and protect the brain in models of mania and depression. The aim of the present study was to evaluate the effects of sodium butyrate (SB) and valproate (VPA) on behavioral changes, histone deacetylase activity, and the levels of cytokines in an animal model of mania induced by dextroamphetamine (d-AMPH). Wistar rats were first given d-AMPH or saline (Sal) for a period of 14 days, and then, between the 8th and 14th days, the rats were treated with SB, VPA, or Sal. The activity of histone deacetylase and the levels of cytokines (interleukin (IL) IL-4, IL-6, and IL-10 and tumor necrosis factor-alpha (TNF-α)) were evaluated in the frontal cortex and striatum of the rats. The administration of d-AMPH increased the activity of histone deacetylase in the frontal cortex. Administration of SB or VPA decreased the levels of histone deacetylase activity in the frontal cortex and striatum of rats. SB per se increased the levels of cytokines in both of the brain structures evaluated. AMPH increased the levels of cytokines in both of the brain structures evaluated, and VPA reversed this alteration. The effects of SB on d-AMPH-induced cytokine alterations were dependent on the brain structure and the cytokine evaluated. Despite VPA and SB having a similar mechanism of action, both being histone deacetylase inhibitors, they showed different effects on the levels of cytokines. The present study reinforces the need for more research into histone deacetylase inhibitors being used as a possible target for new medications in the treatment of bipolar disorder.

Lithium and Tamoxifen Modulate Behavior and Protein Kinase C Activity in the Animal Model of Mania Induced by Ouabain.

Background: The intracerebroventricular injection of ouabain, a specific inhibitor of the Na+/K+-adenosine-triphosphatase (Na+/K+-ATPase) enzyme, induces hyperactivity in rats in a putative animal model of mania. Several evidences have suggested that the protein kinase C signaling pathway is involved in bipolar disorder. In addition, it is known that protein kinase C inhibitors, such as lithium and tamoxifen, are effective in treating acute mania. Methods: In the present study, we investigated the effects of lithium and tamoxifen on the protein kinase C signaling pathway in the frontal cortex and hippocampus of rats submitted to the animal model of mania induced by ouabain. We showed that ouabain induced hyperlocomotion in the rats. Results: Ouabain increased the protein kinase C activity and the protein kinase C and MARCKS phosphorylation in frontal cortex and hippocampus of rats. Lithium and tamoxifen reversed the behavioral and protein kinase C pathway changes induced by ouabain. These findings indicate that the Na+/K+-ATPase inhibition can lead to protein kinase C alteration. Conclusions: The present study showed that lithium and tamoxifen modulate changes in the behavior and protein kinase C signalling pathway alterations induced by ouabain, underlining the need for more studies of protein kinase C as a possible target for treatment of bipolar disorder.

The different effects of lithium and tamoxifen on memory formation and the levels of neurotrophic factors in the brain of male and female rats.

Lithium (Li) is a mood-stabilizing drug used in the treatment of bipolar disorder (BD). Recently, preclinical studies have demonstrated the potential of tamoxifen (TMX) in the treatment of acute episodes of BD. However, the prolonged use of TMX for mood disorders treatment is controversial. In this study, we evaluated the effects of TMX or Li on cognitive behavior, as well as the levels of neurotrophic factors in the brain of male and female rats. Male and female Wistar rats received administrations of water (control group), TMX or Li via gavage for a period of 28days; the rats were then subjected to the open-field test (to evaluate spontaneous locomotion), and the novel object recognition and step-down inhibitory avoidance tests (to evaluate cognition). The levels of NGF, BDNF and GDNF were evaluated in the hippocampus and frontal cortex of the subject rats. No significant differences were observed in the open-field and inhibitory avoidance tests after drug administration in either the male or female rats. The administration of TMX, but not Li, decreased the recognition index of both the male and female rats in the object recognition test. The chronic administration of TMX decreased, whereas Li increased the levels of BDNF in the hippocampus of both the male and female rats. Tamoxifen decreased the levels of NGF in the hippocampus of female rats. In conclusion, it can be suggested that long-term treatments with TMX can lead to significant cognitive impairments by reducing the levels of neurotrophic factors in the brain of rats.

Lithium ameliorates sleep deprivation-induced mania-like behavior, hypothalamic-pituitary-adrenal (HPA) axis alterations, oxidative stress and elevations of cytokine concentrations in the brain and serum of mice.

OBJECTIVES: The goal of the present study was to investigate the effects of lithium administration on behavior, oxidative stress parameters and cytokine levels in the periphery and brain of mice subjected to an animal model of mania induced by paradoxical sleep deprivation (PSD). METHODS: Male C57 mice were treated with saline or lithium for 7 days. The sleep deprivation protocol started on the 5th day during for the last 36 hours of the treatment period. Immediately after the sleep deprivation protocol, animals locomotor activity was evaluated and serum and brain samples was extracted to evaluation of corticosterone and adrenocorticotropic hormone circulating levels, oxidative stress parameters and citokynes levels. RESULTS: The results showed that PSD induced hyperactivity in mice, which is considered a mania-like behavior. PSD increased lipid peroxidation and oxidative damage to DNA, as well as causing alterations to antioxidant enzymes in the frontal cortex, hippocampus and serum of mice. In addition, PSD increased the levels of cytokines in the brains of mice. Treatment with lithium prevented the mania-like behavior, oxidative damage and cytokine alterations induced by PSD. CONCLUSIONS: Improving our understanding of oxidative damage in biomolecules, antioxidant mechanisms and the inflammatory system - alterations presented in the animal models of mania - is important in helping us to improve our knowledge concerning the pathophysiology of BD, and the mechanisms of action employed by mood stabilizers.

Lithium and valproate act on the GSK-3ß signaling pathway to reverse manic-like behavior in an animal model of mania induced by ouabain.

The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on the PI3K/Akt signaling pathway in the brains of rats subjected to the ouabain (OUA)-induced animal model of mania. In addition, the effects of AR-A014418, a GSK-3ß inhibitor, on manic-like behavior induced by OUA were evaluated. In the first experimental protocol Wistar rats received a single ICV injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li or VPA twice a day. In the second experimental protocol, rats received OUA, aCSF, OUA plus AR-A014418, or aCSF plus AR-A014418. On the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, we analyzed the levels of p-PI3K, p-MAPK, p-Akt, and p-GSK-3ß in the brain of rats by immunoblot. Li and VPA reversed OUA-related hyperactivity. OUA decreased p-PI3K, p-Akt and p-GSK-3ß levels. Li and VPA improved these OUA-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. In addition, AR-A014418 reversed the manic-like behavior induced by OUA. These findings suggest that the manic-like effects of ouabain are associated with the activation of GSK-3ß, and that Li and VPA exert protective effects against OUA-induced inhibition of the GSK-3ß pathway.

Sodium butyrate has an antimanic effect and protects the brain against oxidative stress in an animal model of mania induced by ouabain.

Studies have consistently reported the participation of oxidative stress in bipolar disorder (BD). Evidence indicates that epigenetic regulations have been implicated in the pathophysiology of mood disorders. Considering these evidences, the present study aimed to investigate the effects of sodium butyrate (SB), a histone deacetylase (HDAC)inhibitor, on manic-like behavior and oxidative stress parameters (TBARS and protein carbonyl content and SOD and CAT activities) in frontal cortex and hippocampus of rats subjected to the animal model of mania induced by intracerebroventricular (ICV) ouabain administration.The results showed that SB reversed ouabain-induced hyperactivity, which represents a manic-like behavior in rats. In addition, the ouabain ICV administration induced oxidative damage to lipid and protein and alters antioxidant enzymes activity in all brain structures analyzed. The treatment with SB was able to reversesboth behavioral and oxidative stress parameters alteration induced by ouabain.In conclusion, we suggest that SB can be considered a potential new mood stabilizer by acts on manic-like behavior and regulatesthe antioxidant enzyme activities, protecting the brain against oxidative damage.

Sodium Butyrate, a Histone Deacetylase Inhibitor, Reverses Behavioral and Mitochondrial Alterations in Animal Models of Depression Induced by Early- or Late-life Stress.

The aim of the present study was to evaluate the effects of sodium butyrate on depressive-like behavior and mitochondrial alteration parameters in animal models of depression induced by maternal deprivation or chronic mild stress in Wistar rats. maternal deprivation was established by separating pups from their mothers for 3 h daily from postnatal day 1 to day 10. Chronic mild stress was established by water deprivation, food deprivation, restraint stress, isolation and flashing lights. Sodium butyrate or saline was administered twice a day for 7 days before the behavioral tests. Depressive behavior was evaluated using the forced swim test. The activity of tricarboxylic acid cycle enzymes (succinate dehydrogenase and malate dehydrogenase) and of mitochondrial chain complexes (I, II, II-III and IV) was measured in the striatum of rats. From these analyses it can be observed that sodium butyrate reversed the depressive-like behavior observed in both animal models of depression. Additionally, maternal deprivation and chronic mild stress inhibited mitochondrial respiratory chain complexes and increased the activity of tricarboxylic acid cycle enzymes. Sodium butyrate treatment reversed -maternal deprivation and chronic mild stress- induced dysfunction in the striatum of rats. In conclusion, sodium butyrate showed antidepressant effects in maternal deprivation and chronic mild stress-treated rats, and this effect can be attributed to its action on the neurochemical pathways related to depression.

Effects of mood stabilizers on oxidative stress-induced cell death signaling pathways in the brains of rats subjected to the ouabain-induced animal model of mania: Mood stabilizers exert protective effects against ouabain-induced activation of the cell death pathway.

The present study aimed to investigate the effects of mood stabilizers, specifically lithium (Li) and valproate (VPA), on mitochondrial superoxide, lipid peroxidation, and proteins involved in cell death signaling pathways in the brains of rats subjected to the ouabain-induced animal model of mania. Wistar rats received Li, VPA, or saline twice a day for 13 days. On the 7th day of treatment, the animals received a single intracerebroventricular injection of ouabain or aCSF. After the ICV injection, the treatment with mood stabilizers continued for 6 additional days. The locomotor activity of rats was measured using the open-field test. In addition, we analyzed oxidative stress parameters, specifically levels of phosphorylated p53 (pp53), BAX and Bcl-2 in the brain of rats by immunoblot. Li and VPA reversed ouabain-related hyperactivity. Ouabain decreased Bcl-2 levels and increased the oxidative stress parameters BAX and pp53 in the brains of rats. Li and VPA improved these ouabain-induced cellular dysfunctions; however, the effects of the mood stabilizers were dependent on the protein and brain region analyzed. These findings suggest that the Na(+)/K(+)-ATPase can be an important link between oxidative damage and the consequent reduction of neuronal and glial density, which are both observed in BD, and that Li and VPA exert protective effects against ouabain-induced activation of the apoptosis pathway.

The effects of n-acetylcysteine and/or deferoxamine on manic-like behavior and brain oxidative damage in mice submitted to the paradoxal sleep deprivation model of mania.

Bipolar disorder (BD) is a severe psychiatric disorder associated with social and functional impairment. Some studies have strongly suggested the involvement of oxidative stress in the pathophysiology of BD. Paradoxal sleep deprivation (PSD) in mice has been considered a good animal model of mania because it induces similar manic-like behavior, as well as producing the neurochemical alterations which have been observed in bipolar patients. Thus, the objective of the present study was to evaluate the effects of the antioxidant agent's n-acetylcysteine (Nac) and/or deferoxamine (DFX) on behavior and the oxidative stress parameters in the brains of mice submitted to the animal model of mania induced by PSD. The mice were treated for a period of seven days with saline solution (SAL), Nac, DFX or Nac plus DFX. The animals were subject to the PSD protocol for 36 h. Locomotor activity was then evaluated using the open-field test, and the oxidative stress parameters were subsequently evaluated in the hippocampus and frontal cortex of mice. The results showed PSD induced hyperactivity in mice, which is considered a manic-like behavior. In addition to this, PSD increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of mice. The Nac plus DFX adjunctive treatment prevented both the manic-like behavior and oxidative damage induced by PSD. Improving our understanding relating to oxidative damage in biomolecules, and the antioxidant mechanisms presented in the animal models of mania are important in helping to improve our knowledge concerning the pathophysiology and development of new therapeutical treatments for BD.