RESUMEN
Recently, several studies have emerged suggesting a role of the intracellular survival pathways in the treatment of mood disorders. In addition, the beneficial effects of using a combination of antipsychotics and antidepressants have been shown. With this in mind, we evaluated the effects of the acute administration of fluoxetine (FLX), olanzapine (OLZ) and the combination of fluoxetine/olanzapine on the brain-derived-neurotrophic factor (BDNF), cAMP response element-binding (CREB), Protein Kinase B (PKB, Akt), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated death promoter (BAD) in the rat brain. Adult Wistar rats received an acute injection of OLZ (3 or 6 mg/kg) and/or FLX (12.5 or 25 mg/kg), and were evaluated for Akt, BDNF, CREB, Bcl-2 and BAD protein levels in the prefrontal cortex, hippocampus and striatum. Our results showed that treatment with FLX and OLZ alone or in combination increased the Akt, CREB, BDNF, Bcl-2 and BAD levels in the prefrontal cortex, hippocampus and striatum. However, the combination of FLX and OLZ at high doses was associated with a greater increase in the levels of Akt in the prefrontal cortex, and did not have an effect on the levels of BAD in any of the brain areas that we evaluated. Finally, these findings further support the hypothesis that treatment with FLX and OLZ alone or in combination exert neuroprotective effects, and that intracellular survival pathways could be involved in the therapeutic effects of combining antipsychotic and antidepressant drugs in mood disorders.
Asunto(s)
Benzodiazepinas/administración & dosificación , Fluoxetina/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Transducción de Señal/efectos de los fármacos , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Sinergismo Farmacológico , Masculino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Wistar , Proteína Letal Asociada a bcl/metabolismoRESUMEN
BACKGROUND: In experimental models, hypothalamic inflammation is an early and determining factor in the installation and progression of obesity. Pharmacological and gene-based approaches have proven efficient in restraining inflammation and correcting the obese phenotypes. However, the role of nutrients in the modulation of hypothalamic inflammation is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that, in a mouse model of diet-induced obesity, partial substitution of the fatty acid component of the diet by flax seed oil (rich in C18:3) or olive oil (rich in C18:1) corrects hypothalamic inflammation, hypothalamic and whole body insulin resistance, and body adiposity. In addition, upon icv injection in obese rats, both ω3 and ω9 pure fatty acids reduce spontaneous food intake and body mass gain. These effects are accompanied by the reversal of functional and molecular hypothalamic resistance to leptin/insulin and increased POMC and CART expressions. In addition, both, ω3 and ω9 fatty acids inhibit the AMPK/ACC pathway and increase CPT1 and SCD1 expression in the hypothalamus. Finally, acute hypothalamic injection of ω3 and ω9 fatty acids activate signal transduction through the recently identified GPR120 unsaturated fatty acid receptor. CONCLUSIONS/SIGNIFICANCE: Unsaturated fatty acids can act either as nutrients or directly in the hypothalamus, reverting diet-induced inflammation and reducing body adiposity. These data show that, in addition to pharmacological and genetic approaches, nutrients can also be attractive candidates for controlling hypothalamic inflammation in obesity.
Asunto(s)
Grasas Insaturadas en la Dieta/administración & dosificación , Hipotálamo/efectos de los fármacos , Inflamación/prevención & control , Obesidad/prevención & control , Animales , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/efectos adversos , Ingestión de Alimentos/efectos de los fármacos , Ácidos Grasos/sangre , Ácidos Grasos/química , Ácidos Grasos/metabolismo , Ácidos Grasos Omega-3/administración & dosificación , Expresión Génica/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/patología , Immunoblotting , Inflamación/sangre , Inflamación/etiología , Resistencia a la Insulina , Masculino , Ratones , Proteínas del Tejido Nervioso/genética , Obesidad/etiología , Obesidad/fisiopatología , Aceite de Oliva , Aceites de Plantas/administración & dosificación , Proopiomelanocortina/genética , Ratas , Ratas Wistar , Receptores Acoplados a Proteínas G/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
INTRODUÇÃO: A deficiência na captação de glicose em tecidos periféricos e o aumento da gliconeogênese hepática são fenômenos fisiopatológicos observados em pacientes diabéticos do tipo 2. O exercício físico é considerado um importante aliado para a melhora do perfil glicêmico em pacientes diabéticos; entretanto, os mecanismos envolvidos nesse processo não estão completamente elucidados. OBJETIVO: Avaliar o papel da proteína AMPK no controle glicêmico em camundongos diabéticos após o exercício físico. MÉTODOS: Durante o jejum, o teste de tolerância à insulina (ITT) e a técnica de Western blot foram combinados para avaliar a homeostase da glicose em camundongos diabéticos (ob/ob e db/db) submetidos a uma única sessão de natação. RESULTADOS: A hiperglicemia de jejum, a severa resistência à insulina e a deficiência na sinalização da via AMPK/ACC no músculo e no fígado observadas nos camundongos diabéticos foram revertidas após a sessão de exercício. A restauração da via AMPK/ACC reduziu a expressão da enzima gliconeogênica PEPCK no fígado e aumentou a translocação do GLUT4 no músculo esquelético. Esses dados apontam que a ativação da via AMPK/ACC induzida pelo exercício físico é importante para a redução da glicemia de jejum em modelos experimentais de diabetes tipo 2. Esses dados abrem novas frentes para o entendimento de como a atividade física controla da homeostase da glicose em pacientes diabéticos.
INTRODUCTION: The deficiency in glucose uptake in peripheral tissues and increased hepatic gluconeogenesis are physiopathological phenomena observed in type 2 diabetes patients. Physical exercise plays an important role in the improvement of glycemic profile in diabetic patients; however, the mechanisms involved in these processes have not been fully elucidated. OBJECTIVE: to assess the role of AMPK protein in the glycemic control of diabetic mice after exercise. METHODS: During fasting condition, the insulin tolerance test (ITT) and Western blot technique, were combined to assess the glucose homeostasis in diabetic mice (ob/ob and db/db) after a single swimming session. RESULTS: Fasting hyperglycemia, severe insulin resistance and deficiency in the AMPK/ACC signaling in muscle and liver observed in the diabetic mice were reversed after the exercise session. The restoration of AMPK/ACC signaling reduced the expression of the gluconeogenic enzyme, PEPCK in the liver, and increased the translocation of GLUT4 in the skeletal muscle. These data indicate that the activation of AMPK/ACC pathway induced by physical exercise is important to reduce fasting glucose levels in experimental models of type 2 diabetes. These data open new insights for determination of physical activity control on the glucose homeostasis in diabetic patients.