RESUMO
This study aimed to evaluate Haloperidol's (Hal) effects on the behavioral, neurotrophic factors, and epigenetic parameters in an animal model of schizophrenia (SCZ) induced by ketamine (Ket). Injections of Ket or saline were administered intraperitoneal (once a day) between the 1st and 14th days of the experiment. Water or Hal was administered via gavage between the 8th and 14th experimental days. Thirty minutes after the last injection, the animals were subjected to behavioral analysis. The activity of DNA methyltransferase (DNMT), histone deacetylase (HDAC), and histone acetyltransferase and levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and glial-derived neurotrophic factor (GDNF) were evaluated in the frontal cortex, hippocampus, and striatum. Ket increased the covered distance and time spent in the central area of the open field, and Hal did not reverse these behavioral alterations. Significant increases in the DNMT and HDAC activities were detected in the frontal cortex and striatum from rats that received Ket, Hal, or a combination thereof. Besides, Hal per se increased the activity of DNMT and HDAC in the hippocampus of rats. Hal per se or the association of Ket plus Hal decreased BDNF, NGF, NT-3, and GDNF, depending on the brain region and treatment regimen. The administration of Hal can alter the levels of neurotrophic factors and the activity of epigenetic enzymes, which can be a factor in the development of effect collateral in SCZ patients. However, the precise mechanisms involved in these alterations are still unclear.
Assuntos
Ketamina , Esquizofrenia , Humanos , Ratos , Animais , Haloperidol/farmacologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética , Ketamina/toxicidade , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Fator de Crescimento Neural/genética , Modelos Animais de Doenças , Epigênese GenéticaRESUMO
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.
Assuntos
Antimaníacos , Privação do Sono , Anfetamina , Animais , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Modelos Animais de Doenças , Epigênese Genética , Masculino , Mania , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Wistar , Sono REMRESUMO
BACKGROUND: Bipolar Disorder (BD) is a chronic psychiatric disorder characterized by mood disturbances that include depressive, manic, and hypomanic episodes. Despite the severity of the symptoms, there is still a gap in the literature on the precise neurobiology and treatment of BD. The investigations of inflammatory changes in BD has increased in the last decade, evincing the importance of its role in the pathophysiology of the disorder. The present study aimed to investigate the inflammatory role in BD, through the evaluation of biomarkers and their relation to biological rhythms. METHODS: It was conducted a case-control study that included 36 BD and 46 healthy controls (HC). The Cyclooxygenase 2 (COX-2) enzyme, Arachidonic Acid (AA), interleukins (IL) IL-4, IL-5, IL-6, IL-10, IL-33, and Tumor Necrosis Factor Alpha (TNF-α) in the serum of individuals. It also was administered the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN) to the BD and healthy control groups. RESULTS: The results indicated that the individuals with BD showed increased COX-2, AA, IL-6, and TNF-α levels in comparison to the HC without psychiatric disorders, as well as significant commitments in all domains evaluated by BRIAN. LIMITATIONS: Uncontrolled pharmacotherapy used by the included bipolar participants, which had important effects on participants' inflammatory systems and the lack of cases with bipolar manic episodes. CONCLUSIONS: The results of the present study reaffirm that inflammation has an important role in BD, as well as the significant changes in biological rhythms. It is still necessary to better characterize the inflammatory pathway of AA.
Assuntos
Transtorno Bipolar , Biomarcadores , Estudos de Casos e Controles , Humanos , Periodicidade , Fator de Necrose Tumoral alfaRESUMO
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.
Assuntos
Comportamento Animal/efeitos dos fármacos , Ácido Butírico/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Mania/induzido quimicamente , Mania/tratamento farmacológico , Ouabaína/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Ácido Valproico/administração & dosagem , Animais , Transtorno Bipolar/tratamento farmacológico , Ácido Butírico/farmacologia , Corpo Estriado/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Histona Acetiltransferases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento , Ácido Valproico/farmacologiaRESUMO
Evaluate the efficacy of folic acid (FA) as a therapeutic adjunct to lithium (Li) on the manic-like behaviors as well as parameters of oxidative stress and inflammation in an animal model of mania induced by m-amphetamine (m-AMPH). Wistar rats first received m-AMPH or saline (NaCl 0.9%, Sal) for 14 days. Between the 8th and 14th day, rats were treated with water, Li, FA or a combination of thereof drugs (Li + FA). Manic-like behaviors were assessed in the open-field test. Oxidative stress and inflammation parameters were assessed in the frontal cortex, striatum, and hippocampus. Administration of m-AMPH in rats significantly enhanced the exploratory and locomotor behaviors, as well as the risk-taking and stereotypic behaviors. Li + FA reversed these behavioral alterations elicited by m-AMPH. Administration of this psychostimulant also increased oxidative damage to lipids and proteins, whereas Li + FA reversed these oxidative damages. m-AMPH also induced an increase in the glutathione peroxidase (GPx) activity and a decrease in the glutathione reductase (GR) activity. Li + FA reversed the alteration in GR activity, but not in GPx activity. In addition, m-AMPH increased the IL-1ß and TNF-α levels in the rat brain; Li + FA combined therapy reversed the alterations on these inflammatory parameters. FA administration per se reduced the increased TNF-α content induced by m-AMPH. Present study provides evidence that FA is effective as an adjunct to Li standard therapy on manic-like behaviors, oxidative stress and inflammatory parameters in a model of mania induced by m-AMPH.
Assuntos
Antimaníacos/administração & dosagem , Ácido Fólico/administração & dosagem , Mediadores da Inflamação/antagonistas & inibidores , Lítio/administração & dosagem , Mania/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Anfetamina/toxicidade , Animais , Estimulantes do Sistema Nervoso Central/toxicidade , Modelos Animais de Doenças , Quimioterapia Combinada , Mediadores da Inflamação/metabolismo , Masculino , Mania/induzido quimicamente , Mania/metabolismo , Estresse Oxidativo/fisiologia , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antimaníacos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Celecoxib/uso terapêutico , Compostos de Lítio/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Antimaníacos/administração & dosagem , Transtorno Bipolar/induzido quimicamente , Celecoxib/administração & dosagem , Dextroanfetamina/administração & dosagem , Modelos Animais de Doenças , Dopamina/metabolismo , Quimioterapia Combinada , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Compostos de Lítio/administração & dosagem , Masculino , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
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.
Assuntos
Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Ouabaína/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Injeções Intraventriculares , Compostos de Lítio/farmacologia , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos WistarRESUMO
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.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Estresse Oxidativo , Tamoxifeno/farmacologia , Animais , Transtorno Bipolar/fisiopatologia , Modelos Animais de Doenças , Masculino , Ouabaína/administração & dosagem , Ratos , Ratos Wistar , Moduladores Seletivos de Receptor Estrogênico/farmacologiaRESUMO
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.
Assuntos
Comportamento Animal , Transtorno Bipolar/enzimologia , Transtorno Bipolar/patologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Estresse Oxidativo , Aldeídos/metabolismo , Animais , Antioxidantes/metabolismo , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/fisiopatologia , Catalase/metabolismo , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ratos Wistar , Partículas Submitocôndricas/efeitos dos fármacos , Partículas Submitocôndricas/metabolismo , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Tiazóis/administração & dosagem , Tiazóis/farmacologia , Tirosina/análogos & derivados , Tirosina/metabolismo , Ureia/administração & dosagem , Ureia/análogos & derivados , Ureia/farmacologiaRESUMO
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.
Assuntos
Animais , Masculino , Feminino , Extratos Vegetais/farmacologia , Cognição/efeitos dos fármacos , Hypericum , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Fatores de Crescimento Neural/análise , Extratos Vegetais/administração & dosagem , Distribuição Aleatória , Fatores Sexuais , Resultado do Tratamento , Ratos Wistar , Modelos Animais , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Memória/efeitos dos fármacos , Fatores de Crescimento Neural/efeitos dos fármacosRESUMO
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.
Assuntos
Cognição/efeitos dos fármacos , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Hypericum , Fatores de Crescimento Neural/análise , Extratos Vegetais/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Modelos Animais , Fatores de Crescimento Neural/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Distribuição Aleatória , Ratos Wistar , Fatores Sexuais , Resultado do TratamentoRESUMO
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.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Citocinas/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Animais , Antimaníacos/uso terapêutico , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Dextroanfetamina , Modelos Animais de Doenças , Inibidores de Histona Desacetilases/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
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.
Assuntos
Transtorno Bipolar , Encéfalo/metabolismo , Citocinas/sangue , Compostos de Lítio/farmacologia , Estresse Oxidativo , Privação do Sono/complicações , Hormônio Adrenocorticotrópico/sangue , Animais , Antimaníacos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/etiologia , Transtorno Bipolar/metabolismo , Corticosterona/sangue , Modelos Animais de Doenças , Hipercinese/metabolismo , Hipercinese/prevenção & controle , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Esforço Físico/efeitos dos fármacos , Resultado do TratamentoRESUMO
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.
Assuntos
Antimaníacos/farmacologia , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/imunologia , Encéfalo/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Compostos de Lítio/farmacologia , Atividade Motora/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/tratamento farmacológico , Encéfalo/imunologia , Estimulantes do Sistema Nervoso Central/toxicidade , Citocinas/líquido cefalorraquidiano , Citocinas/imunologia , Dextroanfetamina/toxicidade , Modelos Animais de Doenças , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/imunologia , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Hipercinese/imunologia , Interleucina-10/líquido cefalorraquidiano , Interleucina-10/imunologia , Interleucina-1beta/líquido cefalorraquidiano , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Interleucina-4/líquido cefalorraquidiano , Interleucina-4/imunologia , Interleucina-6/líquido cefalorraquidiano , Interleucina-6/imunologia , Compostos de Lítio/uso terapêutico , Masculino , Atividade Motora/imunologia , Neostriado/efeitos dos fármacos , Neostriado/imunologia , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Bipolar Disorder (BD) is one of the most severe psychiatric disorders. 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 manic-like behaviors. Neurotrophins have been considered important mediators in the pathophysiology of BD. The present study aims to investigate the effects of lithium (Li), valproate (VPA), and sodium butyrate (SB), an HDAC inhibitor, on BDNF, NGF and GDNF in the brain of rats subjected to an animal model of mania induced by ouabain. Wistar rats received a single ICV injection of ouabain or artificial cerebrospinal fluid. From the day following ICV injection, the rats were treated for 6 days with intraperitoneal injections of saline, Li, VPA or SB twice a day. In the 7th day after ouabain injection, locomotor activity was measured using the open-field test. The BDNF, NGF and GDNF levels were measured in the hippocampus and frontal cortex by sandwich-ELISA. Li, VPA or SB treatments reversed ouabain-related manic-like behavior. Ouabain decreased BDNF, NGF and GDNF levels in hippocampus and frontal cortex of rats. The treatment with Li, VPA or SB reversed these impairment induced by ouabain. In addition, Li, VPA and SB per se increased NGF and GDNF levels in hippocampus of rats. Our data support the notion that neurotrophic factors play a role in BD and in the mechanisms of the action of Li, VPA and SB.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ácido Butírico/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Locomoção/efeitos dos fármacos , Fator de Crescimento Neural/metabolismo , Afeto/efeitos dos fármacos , Animais , Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/metabolismo , Transtorno Bipolar/psicologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Antagonistas dos Receptores Histamínicos/farmacologia , Compostos de Lítio/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ouabaína/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Resultado do Tratamento , Ácido Valproico/farmacologiaRESUMO
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.
Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Transtorno Bipolar/metabolismo , Transtorno Bipolar/psicologia , Encéfalo/metabolismo , Ácido Butírico/farmacologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Lítio/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Ouabaína/toxicidade , Ratos , Ratos Wistar , Ácido Valproico/farmacologiaRESUMO
Fenproporex (Fen) is an amphetamine-based anorectic; amphetamine use causes a broad range of severe cognitive deficits and anxiogenic-like effects. In this study we evaluated pharmacological effects of the chronic administration of Fen on cognitive and non-cognitive behaviors. Male adult Wistar rats received intraperitoneal administration of vehicle (control group) or Fen (6.25, 12.5 or 25 mg/kg) for 14 days; the animals were then subjected to habituation and object recognition tasks in open-field apparatus, and elevated plus-maze task. The administration of Fen (12.5 and 25 mg/kg) impaired habituation during the second exposure to the habituation task. In addition, the same doses of Fen also impaired the performance in object recognition task. In elevated plus-maze task, the administration of Fen (in all doses tested) induced anxiogenic-like effects in rats. Our results suggest that chronic Fen administration alters memory and induces anxiogenic-like effects in rats.
Assuntos
Anfetaminas/farmacologia , Depressores do Apetite/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Relação Dose-Resposta a Droga , Habituação Psicofisiológica/efeitos dos fármacos , Injeções Intraperitoneais , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
The effects of modafinil (MD) on behavioral and oxidative damage to protein and lipid in the brain of rats were evaluated. Wistar rats were given a single administration by gavage of water or MD (75, 150, or 300 mg/kg). Behavioral parameters were evaluated in open-field apparatus 1, 2, and 3 h after drug administration. Thiobarbituric acid reactive substances (TBARS) and protein carbonyl formation were measured in the brain. MD increased locomotor activity at the highest dose 1 and 3 h after administration. MD administration at the dose of 300 mg/kg increased visits to the center of open-field 1 h after administration; however, 3 h after administration, all administered doses of MD increased visits to the open-field center. MD 300 mg/kg increased lipid damage in the amygdala, hippocampus, and striatum. Besides, MD increased protein damage in the prefrontal cortex, amygdala, and hippocampus; however, this effect varies depending on the dose administered. In contrast, the administration of MD 75 and 300 mg/kg decreased the protein damage in the striatum. This study demonstrated that the MD administration induces behavioral changes, which was depending on the dose used. In addition, the effects of MD on oxidative damage parameters seemed to be in specific brain region and doses.
Assuntos
Compostos Benzidrílicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Masculino , Modafinila , Carbonilação Proteica/efeitos dos fármacos , Ratos , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Promotores da Vigília/farmacologiaRESUMO
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.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/metabolismo , Citocinas/metabolismo , Ouabaína/uso terapêutico , Animais , Antidepressivos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Ouabaína/farmacologia , RatosRESUMO
Objectives: Fenproporex is an amphetamine-based anorectic which is rapidly converted into amphetamine in vivo. Na+, K+-ATPase is a membrane-bound enzyme necessary to maintain neuronal excitability. Considering that the effects of fenproporex on brain metabolism are poorly known and that Na+, K+-ATPase is essential for normal brain function, this study sought to evaluate the effect of this drug on Na+, K+-ATPase activity in the hippocampus, hypothalamus, prefrontal cortex, and striatum of young rats. Methods: Young male Wistar rats received a single injection of fenproporex (6.25, 12.5, or 25 mg/kg intraperitoneally) or polysorbate 80 (control group). Two hours after the last injection, the rats were killed by decapitation and the brain was removed for evaluation of Na+, K+-ATPase activity. Results: Fenproporex decreased Na+, K+-ATPase activity in the striatum of young rats at doses of 6.25, 12.5, and 25 mg/kg and increased enzyme activity in the hypothalamus at the same doses. Na+, K+-ATPase activity was not affected in the hippocampus or prefrontal cortex. Conclusion: Fenproporex administration decreased Na+, K+-ATPase activity in the striatum even in low doses. However, in the hypothalamus, Na+, K+-ATPase activity was increased. Changes in this enzyme might be the result of the effects of fenproporex on neuronal excitability. .