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1.
Transl Psychiatry ; 9(1): 297, 2019 11 13.
Article in English | MEDLINE | ID: mdl-31723123

ABSTRACT

The present study intends to investigate the effect of lithium (Li) and celecoxib (Cel) coadministration on the behavioral status and oxidative stress parameters in a rat model of mania induced by dextroamphetamine (d-AMPH). Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on the 8th day of treatment, rats received lithium (Li), celecoxib (Cel), Li plus Cel, or water until day 14. Levels of oxidative stress parameters were evaluated in the serum, frontal cortex, and hippocampus. d-AMPH administration induced hyperlocomotion in rats, which was significantly reversed by Li and Cel coadministration. In addition, d-AMPH administration induced damage to proteins and lipids in the frontal cortex and hippocampus of rats. All these impairments were reversed by treatment with Li and/or Cel, in a way dependent on cerebral area and biochemical analysis. Li and Cel coadministration reversed the d-AMPH-induced decrease in catalase activity in cerebral structures. The activity of glutathione peroxidase was decreased in the frontal cortex of animals receiving d-AMPH, and treatment with Li, Cel, or a combination thereof reversed this alteration in this structure. Overall, data indicate hyperlocomotion and alteration in oxidative stress biomarkers in the cerebral structures of rats receiving d-AMPH. Li and Cel coadministration can mitigate these modifications, comprising a potential novel approach for BD therapy.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antimanic Agents/therapeutic use , Behavior, Animal/drug effects , Bipolar Disorder/drug therapy , Celecoxib/therapeutic use , Lithium Compounds/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Antimanic Agents/administration & dosage , Bipolar Disorder/chemically induced , Celecoxib/administration & dosage , Dextroamphetamine/administration & dosage , Disease Models, Animal , Dopamine/metabolism , Drug Therapy, Combination , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Lithium Compounds/administration & dosage , Male , Motor Activity/drug effects , Oxidative Stress/drug effects , Rats , Rats, Wistar
2.
Pharmacol Biochem Behav ; 183: 56-63, 2019 08.
Article in English | MEDLINE | ID: mdl-31158395

ABSTRACT

The present study evaluated the effects of the coadministration of lithium (Li) and Cel on inflammatory parameters in an animal model of mania induced by dextroamphetamine (D-amph). It was used Wistar rats 60 days old (250-350 g). The animals (n = 10 per group) received D-amph (2 mg/kg) or saline solution of NaCl 0.9% (Sal) intraperitoneally once a day for 14 days. From day eight until 14, the animals from the D-amph and Sal groups received Li (24 mg/kg), Cel (20 mg/kg), Li + Cel or water via gavage. Behavioral analyses were performed using the open-field test. The levels of IL-1ß, IL-4, IL-10, and TNF-α were evaluated. The administration of D-amph induced hyperactivity in the rats, as well increased the IL-4, IL-10, and TNF-α levels in the serum, frontal cortex, and striatum of rats compared to those of the controls, and treatment with Li plus Cel reversed these alterations. In general, the administration of Li or Cel per se did not have effects on the behavioral and biochemical parameters. However, the treatment with Cel per se decreased only the IL-10 levels in the serum of animals. Besides, the treatment with Li or Cel decreased the IL-4 levels in the serum and reversed the effects of D-amph on this parameter in the frontal cortex. The treatment with Li reversed the effects of D-amph on the TNF-α levels in all tissues evaluated, and the administration of Cel reversed this alteration only in the striatum. It can be observed that treatment with Li plus Cel was more effective against damages caused by D-amph when compared to the administration of both treatments per se, suggesting that the coadministration can be more effective to treat BD rather than Li or Cel itself. The treatment with Li plus Cel was effective against the inflammation induced by D-amph.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antimanic Agents/therapeutic use , Behavior, Animal/drug effects , Bipolar Disorder/chemically induced , Bipolar Disorder/drug therapy , Celecoxib/therapeutic use , Dextroamphetamine/pharmacology , Lithium Compounds/therapeutic use , Analysis of Variance , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Antimanic Agents/administration & dosage , Celecoxib/administration & dosage , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Cytokines/metabolism , Dextroamphetamine/administration & dosage , Disease Models, Animal , Drug Therapy, Combination , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Inflammation/chemically induced , Inflammation/drug therapy , Lithium Compounds/administration & dosage , Male , Rats , Rats, Wistar
3.
Bipolar Disord ; 17(5): 507-17, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25929806

ABSTRACT

OBJECTIVES: Several recent studies have suggested that the physiopathology of bipolar disorder (BD) is related to immune system alterations and inflammation. Lithium (Li) is a mood stabilizer that is considered the first-line treatment for this mood disorder. The goal of the present study was to investigate the effects of Li administration on behavior and cytokine levels [interleukin (IL)-1ß, IL-4, IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α)] in the periphery and brains of rats subjected to an animal model of mania induced by amphetamine (d-AMPH). METHODS: Male Wistar rats were treated with d-AMPH or saline (Sal) for 14 days; on Day 8 of treatment, the rats were administered Li or Sal for the final seven days. Cytokine (IL-1ß, IL-4, IL-6, IL-10, and TNF-α) levels were evaluated in the cerebrospinal fluid (CSF), serum, frontal cortex, striatum, and hippocampus. RESULTS: The present study showed that d-AMPH induced hyperactivity in rats (p < 0.001), and Li treatment reversed this behavioral alteration (p < 0.001). In addition, d-AMPH increased the levels of IL-4, IL-6, IL-10, and TNF-α in the frontal cortex (p < 0.001), striatum (p < 0.001), and serum (p < 0.001), and treatment with Li reversed these cytokine alterations (p < 0.001). CONCLUSIONS: Li modulates peripheral and cerebral cytokine production in an animal model of mania induced by d-AMPH, suggesting that its action on the inflammatory system may contribute to its therapeutic efficacy.


Subject(s)
Antimanic Agents/pharmacology , Behavior, Animal/drug effects , Bipolar Disorder/immunology , Brain/drug effects , Cytokines/drug effects , Lithium Compounds/pharmacology , Motor Activity/drug effects , Animals , Antimanic Agents/therapeutic use , Bipolar Disorder/chemically induced , Bipolar Disorder/drug therapy , Brain/immunology , Central Nervous System Stimulants/toxicity , Cytokines/cerebrospinal fluid , Cytokines/immunology , Dextroamphetamine/toxicity , Disease Models, Animal , Frontal Lobe/drug effects , Frontal Lobe/immunology , Hippocampus/drug effects , Hippocampus/immunology , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Hyperkinesis/immunology , Interleukin-10/cerebrospinal fluid , Interleukin-10/immunology , Interleukin-1beta/cerebrospinal fluid , Interleukin-1beta/drug effects , Interleukin-1beta/immunology , Interleukin-4/cerebrospinal fluid , Interleukin-4/immunology , Interleukin-6/cerebrospinal fluid , Interleukin-6/immunology , Lithium Compounds/therapeutic use , Male , Motor Activity/immunology , Neostriatum/drug effects , Neostriatum/immunology , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/immunology
4.
Mol Neurobiol ; 52(1): 353-62, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25164569

ABSTRACT

Several studies have suggested that alterations in brain-derived neurotrophic factor (BDNF) and increased oxidative stress have a central role in bipolar disorder (BD). Intracerebroventricular (ICV) injection of ouabain (OUA) in rats alters oxidative stress parameters and decreases BDNF levels in the brain. In this context, the present study aims to investigate the effects of BDNF ICV administration on BDNF levels and oxidative stress parameters in brains of rats submitted to animal model of mania induced by OUA. Wistar rats received an ICV injection of OUA, artificial cerebrospinal fluid (ACSF), OUA plus BDNF, or ACSF plus BDNF. Locomotor activity and risk-taking behavior in the rats were measured using the open-field test. In addition, we analyzed the BDNF levels and oxidative stress parameters (TBARS, Carbonyl, CAT, SOD, GR, and GPx) in the frontal cortex and hippocampus of rats. The BDNF was unable to reverse the ouabain-induced hyperactivity and risk-taking behavior. Nevertheless, BDNF treatment increased BDNF levels, modulated the antioxidant enzymes, and protected the OUA-induced oxidative damage in the brain of rats. These results suggest that BDNF alteration observed in BD patients may be associated with oxidative damage, both seen in this disorder.


Subject(s)
Bipolar Disorder/drug therapy , Bipolar Disorder/pathology , Brain-Derived Neurotrophic Factor/administration & dosage , Brain-Derived Neurotrophic Factor/therapeutic use , Brain/pathology , Oxidative Stress , Animals , Bipolar Disorder/physiopathology , Brain/drug effects , Brain/physiopathology , Disease Models, Animal , Hippocampus/enzymology , Hippocampus/pathology , Humans , Injections, Intraventricular , Male , Motor Activity/drug effects , Neuroprotection , Ouabain , Oxidative Stress/drug effects , Rats, Wistar , Thiobarbituric Acid Reactive Substances/metabolism
5.
Pharmacol Biochem Behav ; 128: 89-95, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25433326

ABSTRACT

Studies have revealed alterations in mitochondrial complexes in the brains of bipolar patients. However, few studies have examined changes in the enzymes of the tricarboxylic acid cycle. Several preclinical studies have suggested that histone deacetylase inhibitors may have antimanic effects. The present study aims to investigate the effects of lithium, valproate and sodium butyrate, a histone deacetylase inhibitor, on the activity of tricarboxylic acid cycle enzymes in the brains of rats subjected to an animal model of mania induced by ouabain. Wistar rats received a single intracerebroventricular injection of ouabain or cerebrospinal fluid. Starting on the day following the intracerebroventricular injection, the rats were treated for 7days with intraperitoneal injections of saline, lithium, valproate or sodium butyrate. Risk-taking behavior, locomotor and exploratory activities were measured using the open-field test. Citrate synthase, succinate dehydrogenase, and malate dehydrogenase were examined in the frontal cortex and hippocampus. All treatments reversed ouabain-related risk-taking behavior and hyperactivity in the open-field test. Ouabain inhibited tricarboxylic acid cycle enzymes in the brain, and valproate and sodium butyrate but not lithium reversed this ouabain-induced dysfunction. Thus, protecting the tricarboxylic acid cycle may contribute to the therapeutic effects of histone deacetylase inhibitors.


Subject(s)
Antimanic Agents/pharmacology , Bipolar Disorder/drug therapy , Brain/drug effects , Histone Deacetylase Inhibitors/pharmacology , Animals , Behavior, Animal/drug effects , Bipolar Disorder/metabolism , Bipolar Disorder/psychology , Brain/metabolism , Butyric Acid/pharmacology , Citric Acid Cycle/drug effects , Disease Models, Animal , Energy Metabolism/drug effects , Exploratory Behavior/drug effects , Lithium/pharmacology , Male , Motor Activity/drug effects , Ouabain/toxicity , Rats , Rats, Wistar , Valproic Acid/pharmacology
6.
J Neuroimmunol ; 276(1-2): 236-9, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25288301

ABSTRACT

Bipolar disorder (BD) is a chronic and severe psychiatric disorder and despite its importance, little is known about the precise pathophysiology of this disorder. Several studies have reported that inflammation plays a role in the pathogenesis of BD and that cytokines are altered in these patients. Intracerebroventricular (ICV) injection of ouabain (a potent Na(+)/K(+)-ATPase inhibitor) in rats resulted in manic-like effects and it has been widely used as an animal model of bipolar mania. In this study, we assessed the cytokine levels (IL-1ß, IL-6, IL-10, TNF-α, CINC-1) in the brain structures (hippocampus, striatum, frontal cortex, amygdala), serum and cerebrospinal fluid (CSF) of rats submitted to an animal model of mania induced by ouabain. Our findings demonstrated that ouabain induced hyperlocomotion in rats. However, the only cytokine that showed alteration was IL-6, which was decreased in the striatum after ouabain administration. In conclusion, despite the ouabain administration in rats be a valid model to study the physiopathology of bipolar mania, it seems that this model was not able to mimic the changes in cytokines observed in bipolar patients.


Subject(s)
Antidepressive Agents/therapeutic use , Bipolar Disorder/drug therapy , Bipolar Disorder/metabolism , Cytokines/metabolism , Ouabain/therapeutic use , Animals , Antidepressive Agents/pharmacology , Brain/drug effects , Brain/metabolism , Brain/pathology , Disease Models, Animal , Exploratory Behavior/drug effects , Injections, Intraventricular , Male , Ouabain/pharmacology , Rats
7.
Parasitology ; 141(13): 1761-8, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25111395

ABSTRACT

SUMMARY The aim of this study was to assess the effect of sulfamethoxazole/trimethoprim (ST) supplemented with diphenyl diselenide and sodium selenite in experimental toxoplasmosis, on oxidant/antioxidant biomarkers and cytokine levels. Eighty-four BALB/c mice were divided in seven groups: group A (negative control), and groups B to G (infected). Blood and liver samples were collected on days 4 and 20 post infection (p.i.). Levels of thiobarbituric acid (TBA) reactive substances and advanced oxidation protein products (AOPP) were assessed in liver samples. Both biomarkers were significantly increased in infected groups on day 4 p.i., while they were reduced on day 20 p.i., compared with group A. Glutathione reductase (GR) activity significantly (P<0·01) increased on day 4 p.i., in group G, compared with group A. INF-γ was significantly increased (P<0·001) in both periods, day 4 (groups B, C, F and G) and 20 p.i. (groups C, F and G). IL-10 significantly reduced (P<0·001) on day 4 p.i. in group B; however, in the same period, it was increased (P<0·001) in groups C and G, compared with group A. On day 20 p.i., IL-10 increased (P<0·001) in groups F and G. Therefore, our results highlighted that these forms of selenium, associated with the chemotherapy, were able to reduce lipid peroxidation and protein oxidation, providing a beneficial immunological balance between the production of pro- and anti-inflammatory cytokines.


Subject(s)
Antioxidants/metabolism , Benzene Derivatives/pharmacology , Organoselenium Compounds/pharmacology , Sodium Selenite/pharmacology , Toxoplasmosis/metabolism , Animals , Biomarkers/metabolism , Cytokines/metabolism , Disease Models, Animal , Lipid Peroxidation , Male , Mice , Mice, Inbred BALB C , Oxidants/metabolism , Oxidation-Reduction , Oxidative Stress , Thiobarbituric Acid Reactive Substances/metabolism
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