Efeito dos inibidores da cicloxigenase-2 nas alterações neurocomportamentais, inflamatórias e oxidativas induzidas pela exposição sistêmica a lipopolissacarídeo em camundongos machos

• Ano de defesa: 2020
• Autor(a) principal: Silva, Daniel Moreira Alves da
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Palavras-chave em Português: Depressão; Inflamação
• Link de acesso: http://www.repositorio.ufc.br/handle/riufc/49916

Depression is a very common mood disorder that can often come accompanied by anxiety disorders. Despite advances in the knowledge of its neurobiology, current pharmacological therapy is still based on monoamine theory, which has many limitations. Recent evidence suggests that the pathophysiology of depression may be associated with inflammation. In this context, Celecoxib and Etoricoxib are drugs widely used in clinical practice to relieve inflammation. They are inhibitors of cyclooxygenase 2 (COX-2), an enzyme that is present at inflammation sites being expressed by cells involved in the inflammatory process, such as macrophages and found in other tissues and organs, such as the brain. The literature shows potential beneficial effects on the central nervous system of COX-2 inhibitors in diseases such as bipolar disorder and Alzheimer's. The objective of this study was to evaluate the effects of cycloxygenase-2, Celecoxib (CLX) and Etoricoxib (ETR) inhibitors on neurobehavioral, oxidative and inflammatory changes induced by systemic exposure to Escherichia coli lipopolysaccharide (LPS) in mice. Adult male Swiss mice were used. The animals were submitted to the systemic inflammation model by LPS, where for ten consecutive days they received intraperitoneal injections of LPS 0.5 mg / kg. From day 5 to day 10, animals were treated one hour after LPS with CLX (15 mg / kg), ETR (10 mg / kg) or Fluoxetine (FLU) (20 mg / kg) via oral by gavage. FLU was used as a positive control. Twenty-four hours after the last oral administration of the drug, the animals underwent predictive tests of depressive behavior (forced swimming and tail suspension), anxiolytic effect (elevated cross maze and perforated plate) and activity evaluation (open field). locomotor and brain areas (hippocampus, prefrontal cortex and striated body) were dissected. Oxidative stress parameters (malondialdehyde, nitrite and reduced glutathione) and proinflammatory cytokines (TNF, IL-1B and IL-6) were measured. In addition, in vitro tests were performed on BV2 microglial cell culture to evaluate the neuroprotective effect of these drugs from the nitric oxide dosage. The experiments were performed only after the project was approved by the Animal Use Ethics Committee (CEUA) of the Federal University of Ceará (UFC) filed under CEUA No. 5089270819. The results show that the LPS induced depressive and anxious behavior. CLX and ETR treatment was able to reverse most behavioral changes predictive of depression and anxiety. It was found that treatment with CLX and ETR and exposure to LPS did not affect the spontaneous locomotor activity of the animals. It was evidenced that the degree of lipid peroxidation was decreased in the hippocampus, prefrontal cortex and striated body by CLX and in the prefrontal cortex and striated body by ETR, evidenced by the MDA dosage and the nitrosative stress was reduced in the striated body by CLX. CLX and in the striated body and hippocampus by the ETR. In addition, the endogenous defense system against free radicals was strengthened in the prefrontal cortex, striated body and hippocampus by CLX and ETR, and was evaluated by GSH dosing. CLX and ETR were able to significantly reduce IL-1β and IL-6 levels in the hippocampus and in vitro experiments concluded that CLX has a neuroprotective character from the decrease in nitric oxide production by LPS-exposed microglial cells. These data are expected to broaden information on the role of inflammation in depression and anxiety by listing the use of cyclooxygenase-2 enzyme inhibitors as possible therapeutic options in the treatment of neurobiological psychiatric disorders in inflammation and oxidative stress.