Wilson R. Resende

Lithium and tamoxifen modulate cellular plasticity cascades in animal model of mania

Lithium (Li) is the main mood stabilizer and acts on multiple biochemical targets, leading to neuronal plasticity. Several clinical studies have shown that tamoxifen (TMX) – a protein kinase C (PKC) inhibitor – has been effective in treating acute mania. The present study aims to evaluate the effects of TMX on biochemical targets of Li, such as glycogen synthase kinase-3β (GSK-3β), PKC, PKA, CREB, BDNF and NGF, in the brain of rats subjected to an animal model of mania induced by d-amphetamine (d-AMPH). Wistar rats were treated with d-AMPH (2mg/kg, once a day) or saline (Sal; NaCl 0.9%, w/v), Li (47.5 mg/kg, intraperitoneally (i.p.), twice a day) or TMX (1 mg/kg i.p., twice a day) or Sal in protocols of reversion and prevention treatment. Locomotor behavior was assessed using the open-field task, and protein levels were measured by immunoblot. Li and TMX reversed and prevented d-AMPH-induced hyperactivity. Western blot showed that d-AMPH significantly increased GSK-3 and PKC levels, and decreased pGSK-3, PKA, NGF, BDNF and CREB levels in the structures analyzed. Li and TMX were able to prevent and reverse these changes induced by d-AMPH in most structures evaluated. The present study demonstrated that the PKC inhibitor modulates the alterations in the behavior, neurotrophic and apoptosis pathway induced by d-AMPH, reinforcing the need for more studies of PKC as a possible target for treatment of bipolar disorder.

Effects of sodium butyrate on oxidative stress and behavioral changes induced by administration of d-AMPH

Several evidences have demonstrated that oxidative stress has a central role in bipolar disorder (BD). Recently, studies have been suggested histone deacetylases (HDAC) as a possible target for new medications in treatment of mood disorders. In this study, we investigated the effects of sodium butyrate (SB, a histone deacetilase inhibitor) on oxidative stress in rats submitted to an animal model of mania induced by d-amphetamine (d-AMPH). Wistar rats were first given d-AMPH or saline (Sal) for 14 days, and then, between days 8 and 14, rats were treated with SB or Sal. Locomotor activity and risk-taking behavior were assessed by open-field test and oxidative stress was measured in prefrontal cortex, amygdala, hippocampus and striatum. The results showed that SB reversed and prevented d-AMPH-induced behavioral effects. The d-AMPH administration induced oxidative damage in all brain structures analyzed. Depending on the cerebral area and technique, SB was able to reverse this impairment. The present study reinforces the need for more studies of HDAC inhibitors as possible target for new medications in treatment for BD.

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.

Lithium and valproate modulate energy metabolism in an animal model of mania induced by methamphetamine

Studies have shown alterations in mitochondrial complexes of bipolar disorder (BD) patients. However, changes in the Krebs cycle enzymes have been little studied. The animal model of mania induced by amphetamine has been widely used for the study of bipolar mania. The aim of this study is to assess behavioral and energy metabolism changes in an animal model of mania induced by methamphetamine (m-AMPH). Wistar rats were first given m-AMPH or saline for 14 days, and then, between days 8 and 14, rats were treated with lithium (Li), valproate (VPA), or saline (Sal). Locomotor behavior was assessed using the open-field task and activities of Krebs cycle enzymes (citrate synthase and succinate dehydrogenase), mitochondrial respiratory chain complexes (I, II, III, and IV), and creatine kinase measured in the brain structures (prefrontal, amygdala, hippocampus, and striatum). Li and VPA reversed m-AMPH-induced hyperactivity. The administration of m-AMPH inhibited the activities of Krebs cycle enzymes and complexes of the mitochondrial respiratory chain in all analyzed structures. Li and VPA reversed m-AMPH-induced energetic metabolism dysfunction; however, the effects of Li and VPA were dependent on the brain region analyzed. From the results obtained in this study, we suggested that the decreased Krebs cycle enzymes activity induced by m-AMPH may be inhibiting mitochondrial respiratory chain complexes. Therefore, changes in the Krebs cycle enzymes may also be involved in BD.

Fenproporex increases locomotor activity and alters energy metabolism, and mood stabilizers reverse these changes: a proposal for a new animal model of mania.

Fenproporex (Fen) is converted in vivo into amphetamine, which is used to induce mania-like behaviors in animals. In the present study, we intend to present a new animal model of mania. In order to prove through face, construct, and predictive validities, we evaluated behavioral parameters (locomotor activity, stereotypy activity, and fecal boli amount) and brain energy metabolism (enzymes citrate synthase; malate dehydrogenase; succinate dehydrogenase; complexes I, II, II–III, and IV of the mitochondrial respiratory chain; and creatine kinase) in rats submitted to acute and chronic administration of fenproporex, treated with lithium (Li) and valproate (VPA). The administration of Fen increased locomotor activity and decreased the activity of Krebs cycle enzymes, mitochondrial respiratory chain complexes, and creatine kinase, in most brain structures evaluated. In addition, treatment with mood stabilizers prevented and reversed this effect. Our results are consistent with the literature that demonstrates behavioral changes and mitochondrial dysfunction caused by psychostimulants. These findings suggest that chronic administration of Fen may be a potential animal model of mania.

Effects of sodium butyrate in animal models of mania and depression: implications as a new mood stabilizer.

Bipolar disorder is a severe mood disorder with high morbidity and mortality. Despite adequate treatment, patients continue to have recurrent mood episodes, residual symptoms, and functional impairment. Some preclinical studies have shown that histone deacetylase inhibitors may act on depressive-like and manic-like behaviors. Therefore, the aim of the present study was to evaluate the effects of sodium butyrate (SB) on behavioral changes in animal models of depression and mania. The animals were submitted to protocols of chronic mild stress or maternal deprivation for induction of depressive-like behaviors and subjected to amphetamine, or ouabain administration for induction of manic-like behaviors. SB reversed the depressive-like and manic-like behaviors evaluated in the animal models. From these results we can suggest that SB may be a potential mood stabilizer.

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.

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

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).

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

&NA; 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‐3&bgr; 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‐3&bgr; in the brain of rats by immunoblot. Li and VPA reversed OUA‐related hyperactivity. OUA decreased p‐PI3K, p‐Akt and p‐GSK‐3&bgr; 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‐3&bgr;, and that Li and VPA exert protective effects against OUA‐induced inhibition of the GSK‐3&bgr; pathway. HighlightsOuabain (OUA)‐induced manic‐like behavior in animal model of mania.Mania is clinic march clinical of bipolar disorder; mood stabilizers such as lithium (Li) and valproate (VPA) reversed the manic‐like behavior induced by OUA.Bipolar patients overexpress GSK‐3&bgr;; AR‐A0144818, an inhibitor of GSK‐3&bgr;, reversed the manic‐like behavior induced by OUA.

Evaluation of acetylcholinesterase in an animal model of mania induced by d-amphetamine

The present study aims to investigate the effects of mood stabilizers, lithium (Li) and valproate (VPA), on acetylcholinesterase (AChE) activity in the brains of rats subjected to an animal model of mania induced by D-amphetamine (D-AMPH). In the reversal treatment, Wistar rats were first given D-AMPH or saline (Sal) for 14 days. Between days 8 and 14, the rats were treated with Li, VPA, or Sal. In the prevention treatment, rats were pretreated with Li, VPA, or Sal. AChE activity was measured in the brain structures (prefrontal cortex, hippocampus, and striatum). Li, alone in reversion and prevention treatments, increased AChE activity in the brains of rats. VPA, alone in prevention treatment, increased AChE activity in all brain regions evaluated; in the reversion, only in the prefrontal. However, D-AMPH decreased activity of AChE in the striatum of rats in both the reversion and prevention treatments. VPA was able to revert and prevent this AChE activity alteration in the rat striatum. Our findings further support the notion that the mechanisms of mood stabilizers also involve changes in AChE activity, thus reinforcing the need for more studies to better characterize the role of acetylcholine in bipolar disorder.