Depressão e prejuízo de memória induzidos pela administração de estreptozotocina em camundongos: efeitos terapêuticos do disseleneto de p-clorodifenila

Abstract

Pre-diabetes and diabetes are metabolic diseases of heterogeneous etiopathology including defects in the secretion and action of insulin, or both, the presence of hyperglycemia, glucose and insulin intolerance, disorders of carbohydrate, fat, and protein metabolism, among others. In addition to the metabolic effects, complications of these diseases in the central nervous system (CNS) are known, such as impaired memory, mood disorders, and depression. In animal models, p-dichlorodiphenyl diselenide (p-ClPhSe)2 has positive effects on memory impairment and the depressive-like phenotype. In this sense, this thesis aimed to evaluate the effects of streptozotocin (STZ) administration on memory impairment and the depressive-like phenotype, elucidating the possible mechanisms involved in male Swiss mice. Moreover, the neuroprotective action of (p-ClPhSe)2 in diabetic mice was investigated. Paper 1 demonstrated that (p-ClPhSe)2 treatment, at a dose of 5 mg/kg for 7 days, was effective against memory impairment, which was demonstrated in the object recognition and object location tests in diabetic animals. Although this treatment regimen reduced hyperglycemia on day 21 of the experimental protocol, (p-ClPhSe)2 did not reverse all metabolic parameters characteristics of the diabetic phenotype in mice. On the other hand, (p-ClPhSe)2 had positive effects on the modulation of the hippocampal BDNF/TrkB pathway and neuroprotection, contributing to the promising effects of this compound in behavioral tests. Based on the (p-ClPhSe)2 beneficial effects on hippocampal proteins, other possible effects of (p-ClPhSe)2 concerning the depressive-like phenotype associated with diabetes were investigated. Thus, paper 2 showed that (p-ClPhSe)2 at a dose of 5 mg/kg for 7 days elicited an antidepressant-like effect on tail suspension and forced swimming tests in diabetic mice. Besides, diabetic mice showed oxidative stress and reduced levels of Keap1/Nrf2/HO-1 proteins in the cerebral cortex, as well as an increase in the adrenal gland relative weight and a reduction in the levels of glucocorticoid receptors in the cerebral cortex. The antioxidant effect of (p-ClPhSe)2 and the modulation of the Keap1/Nrf2/HO-1 signaling pathway in the cerebral cortex of mice were also demonstrated. However, the compound was not effective against the parameters determined to characterize the hypothalamic-pituitary-adrenal axis. Besides, to preserve the 3R’s guidelines, those animals, from the protocols described above, that did not present hyperglycemia, after intraperitoneal injection of STZ, were evaluated and characterized as pre-diabetic. These mice showed metabolic alterations such as mild hyperglycemia, reduced body weight and epididymal fat, and increased area under the curve in glucose and insulin tolerance tests when compared to control animals. In this context, the body of manuscript 1 results revealed that pre-diabetic mice had impairment of memory and depressive-like phenotype and that these behaviors were accompanied by the reduction in the hippocampal levels of proteins of the insulin (IRS-1/Akt/GLUT4) and BDNF/CREB pathways. This thesis contributes to our understanding of the mechanisms involved in the pre-diabetes and diabetes in an experimental model induced by STZ. Moreover, it reveals the (p-ClPhSe)2 promising effects on memory impairment and depressive-like phenotype and its actions on hippocampal and cerebral cortical proteins, indicating that this compound may be an alternative to treat the memory-depression dyad associated with diabetes.