Depressão induzida pela administração de dexametasona em camundongos: efeitos terapêuticos do disseleneto de p-clorodifenila

Abstract

Different animal models already reported that the administration of DEX can induce phenotypic behaviors of depression and anxiety, as well as brain molecular changes. However, most studies report on the effects of DEX from pre- and neonatal periods. Besides, most of these studies have as their main focus to evaluate the effects of DEX in the hippocampal zone. Moreover, a connection between the apoptotic signaling in the prefrontal cortex (PFC) of adult Swiss mice and the depressive/anxiogenic behavioral phenotype induced by the subchronic administration of DEX is less reported in the literature. The organoselenium compound p-chloro-diphenyl diselenide (p-ClPhSe)2 shows an antidepressant-like effect in animal models by different action targets. Besides, (p-ClPhSe)2 modulates the glutamatergic neurotransmission and oxidative stress, which play a key role in the pathophysiology of affective disorders. Thereby, the main objective of this thesis was to evaluate the contribution of antioxidant and glutamatergic systems for the pharmacological effects of (p-ClPhSe)2 in a depression model induced by 21 injections of DEX 2mg/kg, as well as to investigate the negative effects of this subchronic administration of DEX in the PFC of adult Swiss mice. The results of article 1 demonstrated that adult Swiss mice exposed to DEX showed a depressive/anxiogenic-like behavioral phenotype followed by alterations in the CPF, such as reduced levels of glucocorticoid receptors and an increase in fluorojade-C positive cells. Moreover, the results of article 1 also demonstrated that the levels of pro- apoptotic protein cleaved caspase-3 and the ratios of PARP cleaved/total and Bax/Bcl-2 were increased in the PFCs of mice after subchronic exposure to DEX. In addition to involvement with pro-apoptotic cell signaling in the PFC, the findings of article 2 demonstrated that adult Swiss mice exposed to DEX showed the depressive-/anxiogenic-like behavioral phenotype followed by increased oxidative stress and dysfunction in the glutamatergic neurotransmission in the PFC. The results from this article showed that the intragastric treatment with (p- ClPhSe)2 during 7 days in the 5 and 10 mg/kg doses reversed the depressive-like behavioral phenotype induced by DEX. In addition, the article 2 revealed the effectiveness of compound in the 1, 5 and 10 mg/kg doses in reducing reactive oxygen species levels, as well as to increase the activity of catalase, in all doses tested, and superoxide dismutase in the 10 mg/kg dose in the PFC of mice exposed to DEX. The article 2 also demonstrated that 10 mg/kg of (p-ClPhSe)2 increased the [3H] glutamate uptake/release and decreased the Na+/K+-ATPase activity, as well as the EAAT1 and NMDA R2A protein contents in the PFC of DEX-exposed mice. Together, the results of this thesis contribute to the understanding of deleterious effects induced by DEX in the PFC of adult Swiss mice. Furthermore, the results reveal that the antioxidant activity and the modulation of the glutamatergic system contribute to the antidepressant-like effect of (p-ClPhSe)2 in adult Swiss mice exposed to DEX with depressive-like phenotype, indicating that this compound may be a therapeutic alternative for the treatment of depression.