Effect of 3B-diol on depression in preimenopause: Behavioral and Neurogenic Assessment

• Grant number: 17/15303-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): November 01, 2017
• Effective date (End): September 02, 2018
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Janete Aparecida Anselmo Franci
• Grantee: Bruna Kalil Cutti
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Perimenopause, the period of transition from reproductive to non-reproductive life, is the period of greater vulnerability of women to depression. There is no consensus on a possible correlation between depression and hormonal changes at this time, but most authors did not find a correlation with estrogen plasma concentrations. In fact, despite the fluctuation of these hormone levels, mean plasma concentrations in perimenopause are not different from those in premenopausal women. Despite this, the literature shows that oestradiol therapy improves many symptoms of perimenopause, an effect not yet understood since women do not present estrogen deficiency in this period. In an animal model of perimenopause (rat), we observed depression-like behaviors, which were prevented by estrogen therapy. In later studies, we observed that although estradiol levels are normal in periestropausal rats, the expression of receptors for beta-estradiol (ER²) is greatly reduced in the dorsal nucleus of the raphe (DRN) which has been corrected by estradiol. Thus, although estrogens are at normal levels in the periestropause, the estradiol sensitivity of central areas associated with mood disorders is decreased. The increased ER² expression induced by estradiol in the DRN facilitated the action of this hormone in this nucleus and increased the number of serotonergic cells, thus increasing serotonin content in the hippocampus. The expression of ER² in the hippocampus also was increased by estradiol. Despite all this benefic effects, estrogen therapy causes dangerous side effects to women's health, such as breast and endometrial cancer due to the activation of receptors alpha for estradiol (ER±). Thus, therapy with specific ER² agonists, such as the 3²-diol proposed in the present project, would have dual advantage: to treat the symptoms of perimenopause and to eliminate side effects. Current evidence indicates that adult hippocampal neurogenesis is necessary for successful antidepressant action. The neurogenic hypothesis postulates that a decrease in hippocampal neurons is correlated with the pathogenesis and pathophysiology of depression and it is known that increased neurogenesis is necessary for the treatment of depression and is also a classic effect of estrogens. Thus, the aim of this study is to evaluate in a perimenopause animal model whether ER² selective agonist therapy, 3²-diol: 1) prevents perimenopausal depression (by forced swimming test), 2) increases production of new neurons (by icc for KI-67) and / or increases neuronal survival (by icc for DCX) of the hippocampus and 3) increases the function (by icc for TPH), proliferation (KI-67), and / or the survival (DCX) of the serotonergic neurons of the DRN. If the hypothesis of preventing depression is confirmed, an important opportunity can be created for the hormonal therapy of women with a family history of breast or endometrial cancer and who exhibit mood changes during perimenopause.