Envolvimento de vias oxidativas, inflamatórias e neurotróficas no efeito antidepressivo do carvedilol em modelo de depressão induzido por estresse crônico imprevisível

Abstract

Depression is a severe and disabling psychiatric disorder that affects people of all socioeconomic classes, ethnicities and ages. Oxidative stress, neuroinflammation and the deficit of neurotrophic factors have been highlighted as justification for the symptoms and therapeutic failure in depression. Based on assumption that carvedilol (CVD) present antioxidant and anti-inflammatory properties, was proposed to evaluate the behavioral and neurochemical effects of repeated CVD administration in the model of depression induced by chronic unpredictable stress (CUS). For the induction of depression female Swiss mice (30-32g) were submitted, during 21 days, to different stressors. Between days 15 and 21 the animals received either CVD (5 or 10mg/kg) or desvenlafaxine (DVS 10mg/kg) orally. On the 22nd day, the animals were submitted to the following behavioral tests: open field, elevated plus maze, hole board, tail suspension, splash, social interaction and Y-maze. Shortly after the behavioral tests, the animals were euthanized and the cerebral areas of the prefrontal cortex (CPF) and hippocampus (HC) were dissected for the evaluation of oxidative stress [measurement of thiobarbituric acid reactive species (malondialdehyde - MDA), reduced glutathione (GSH) and nitrite], myeloperoxidase activity (MPO), cytokine concentrations (IL-4, IL-6 and IFN-γ) and Brain Derived Neurotrophic Factor (BDNF). In the open field test, ECI caused a reduction in the number of crossings and an increase in the number of rearing and grooming, while all treatments were able to reverse this effect. In elevated plus maze, CUS caused a decrease in the number of entries and length of stay in the open arms and all treatments also reversed this effect. In addition, the CUS caused a decrease in the number of dips in the hole board, an effect that was reversed by CVD5 and CVD10. The CUS caused an increase in the immobility time in the tail suspension test, while all treatments reversed this effect. In the splash test, CUS increased latency for grooming and decreased the number of grooming, while CVD10 and DVS treatments reversed the observed effect on latency and CVD5 and CVD10 reversed the observed effect on the number of grooming. In addition, CUS caused a reduction in social interaction, while CVD5 and DVS treatments were able to reverse this effect. CUS also caused a cognitive deficit in the Y-maze test that was reversed by DVS or CVD10. In the evaluation of the oxidative stress parameters, the CUS caused reduction of GSH levels only in the hippocampus, while the treatment with DVS and CVD5 increased this marker in PFC and HC and CVD10 exhibited this effect only in the HC. CUS also caused an increase in nitrite concentrations in CPF and HC and all treatments were able to reverse this effect in PFC and HC. In addition, CUS caused an increase in MDA concentrations in PFC and HC, whereas only CVD10 reversed this effect in CPF and DVS, CVD5 and CVD10 reversed this effect in HC. Regarding the MPO enzymatic activity, the CUS increased this parameter in both studied areas, while CVD5 and CVD10 reversed this effect in both areas and DVS only in HC. In the evaluation of cytokines, ECI was able to cause IL-4 reduction in CPF and no treatment studied was able to reverse this effect. About IL-6 levels, treatment with DVS or CVD increased concentrations of this cytokine in both brain areas. CUS caused an increase in IFN-γ concentrations in CPF and only CVD10 was able to reverse this effect. In HC, treatment with DVS caused an increase in IFN-γ concentrations. Furthermore, it was observed a reduction of BDNF concentration in CPF and HC of animals submitted to CUS. At CPF, only CVD10 was able to reverse the effect of CUS on BDNF while CVD at both doses reversed this effect at HC. Together these data show that CVD has an antidepressant effect probably associated with antioxidant, anti-inflammatory and neurotrophic action.