Efeitos farmacológicos do disseleneto de difenila em um modelo de menopausa induzida por ovariectomia em roedores

Abstract

The physiological state of menopause is characterized by an irreversible loss of ovarian function, with a resulting decrease in estrogen production, leading to the appearance of metabolic, cognitive, and behavioral alterations. For this reason, understanding how the decrease in the estrogen production contributes to the progress of menopausal symptoms can be very useful for the development of alternative therapies than hormone replacement therapy. In this context, the data show that ovariectomized Wistar rats treated with (PhSe)2 at a dose of 5 mg/kg once a day for 30 days presented lower plasma triglyceride levels and increased HDL levels when compared to control ones. Moreover, (PhSe)2 administration reduced the weight gain and fat abdominal accumulation induced by ovariectomy. It was also observed that (PhSe)2 treatment improved hepatic oxidative stress parameters in ovariectomized rats (ascorbic acid and reduced glutathione levels, and glutathione S-transferase and catalase activities). Additionally, (PhSe)2 treatment at a dose of 5 mg/kg once a day for 30 days improved the performance of ovariectomized Wistar rats in the Morris Water Maze test, possibly by inhibiting the increase in brain acetylcholinesterase activity induced by ovariectomy. The present results suggest a promising role of (PhSe)2 against the cognitive decline related to menopause. The transition to menopause is associated with an increased risk of depressed mood. On this bases, the obtained results demonstrate that the prolongation of immobility time in the tail suspension test and forced swimming test in ovariectomized mice submitted to subchronic stress protocol was prevented by (PhSe)2 treatment at a dose of 10 mg/kg. It was also found a possible involvement of the serotonin system in this effect, demonstrated by the modulation of 5-HT2A/2C and 5-HT3 receptor subtypes. Although (PhSe)2 had inhibited in vitro monoamine oxidase A and B activities, treatment of ovariectomized mice with (PhSe)2 did not alter neither MAO-A nor MAO-B ex vivo activity. These findings suggest that (PhSe)2 treatment could influence mood and behavior in postmenopausal women. In order to investigate a possible mechanism of action for the hypocholesterolemic effect of (PhSe)2 it was observed that (PhSe)2 treatment increases the LDL receptor levels and augment the adenosine monophosphate (AMP)-activated kinase (AMPK) activation state without inhibiting directly 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme activity in HepG2 cell cultures. These findings are in accordance with those from in vivo studies previously published. In addition, L6 skeletal muscle cells treated with (PhSe)2 presented an augment in glucose transporter 4 (GLUT4) translocation from the cytosol to the cell membrane via an increase in AMPK phosphorylation state, which could be linked to the hypoglycemic properties presented by (PhSe)2 in other studies. In conclusion, the body of evidence presented in this thesis points to the use of (PhSe)2 as a promising alternative therapy for the management of postmenopausal symptoms. However, it is important to mention that the global net effects of (PhSe)2 still need to be better described in order to identify possible negative side effects.