RESUMO
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.