Alterações respiratórias em mitocôndrias derivadas de cérebros de camundongos submetidos ao modelo animal de esquizofrenia induzido por cetamina

• Ano de defesa: 2022
• Autor(a) principal: Tavares, Daniely Sampaio Arruda
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Palavras-chave em Português: Esquizofrenia; Ketamina; Mitocôndrias; Estresse Oxidativo
• Link de acesso: http://www.repositorio.ufc.br/handle/riufc/69813

Schizophrenia is a serious and disabling mental disorder that affects about 24 million people worldwide. This psychiatric disease is increasingly being the subject of studies, due to its characteristics as heterogeneous in terms of mechanisms and multifactorial, as well as great social and economic impact. Schizophrenia is associated with mitochondrial dysfunction and oxidative imbalance. Oxidative imbalance alters cellular pathways, as it alters molecules such as lipids, proteins, and DNA, which is one of the factors related to the progression of diseases. To contribute to the advancement in the understanding of the pathophysiology and possible new targets for the treatment of schizophrenia, the objective of the present work was to evaluate the function of brain mitochondria isolated from animals submitted to the model of schizophrenia induced by repeated administration of ketamine, investigating mitochondrial respiration, influence on the opening of the mitochondrial permeability transition pore (mPTP), alterations caused by oxidative stress and its regulation by the renin-angiotensin system (RAS). For this purpose, adult Swiss mice were treated intraperitoneally (i.p) for 14 days with ketamine (KET group) 20mg/kg or saline (control group). Thirty minutes after the last administration of KET, the animals were submitted to behavioral evaluation by the open field test and euthanized to remove the brains and sequentially isolate the mitochondria. Total protein dosage, mitochondrial respiration/function assessment, mitochondrial swelling (mPTP opening), and quantification of hydrogen peroxide (H2O2) production were performed. Behavioral data showed that repeated exposure to KET induced hyperlocomotion, hyperactivity, and anxiety, thus modeling positive symptoms of schizophrenia. Mitochondria isolated from the brain tissue of animals subjected to KET showed impaired respiration and function. They also increased hydrogen peroxide production, indicating oxidative stress compared to the control group, causing an increase in the antioxidant enzyme superoxide dismutase (SOD). Exposure of isolated mitochondria to angiotensin II and losartan did not cause significant changes in mitochondrial respiration. In conclusion, this study demonstrated that after administration of KET for 14 days, brain mitochondria have inefficient function and respiration, more precisely the inactivity of complex I and II of the mitochondrial electron transport chain (ETC), and greater production of H2O2 determining oxidative stress, corroborating the evidence of mitochondrial dysfunction triggered by NMDA receptor blockade. The methods used in this study are promising to expand research on the relationship between brain mitochondria and schizophrenia, helping to improve the pathophysiology of the disease and thus be able to investigate new mechanisms for pharmacological alternatives, such as angiotensin receptors present in mitochondria and drugs antagonists of this system, to contribute and advance in the treatment of this disease, which remains incurable.