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  • br Introduction Estrogens play an


    Introduction Estrogens play an important role in the Amiloride HCl dihydrate (Arevalo et al., 2015). During several decades, estrogen withdrawal in women has been associated with cognitive impairment, increased Alzheimer\'s disease (AD) risk (Pike, 2017) and with psychiatric disorders such as schizophrenia (Kulkarni et al., 2015), depression (Schmidt et al., 2015) and anorexia nervosa (Ramoz et al., 2013). Interestingly, hormone therapy (HT) has demonstrated beneficial effects on cognition and mood (Luine, 2014), and the use of estradiol as an adjuvant in antipsychotic therapy improves symptoms of schizophrenia in women of child-bearing age (Kulkarni et al., 2015). However, HT has some potential side effects in women, including increased risk for heart disease, breast cancer and stroke (Gurney et al., 2014). In this regard, this caveat led to the development and implementation of more specific molecules, such as Selective Estrogen Receptor Modulators (SERMs) and selective Tissue Estrogenic Activity Regulators (STEARs) (Arevalo et al., 2011; Reed and Kloosterboer, 2004). Tibolone is a synthetic steroid, classified as STEAR, which means that its activation of estrogen receptors in human tissues is dependent on the availability of enzymes in each tissue (Kloosterboer, 2011). Moreover, whereas tibolone actions are mediated by estrogen receptors (ERs) in bone and vagina, it also activates progesterone receptors in endometrial cells (Kloosterboer, 2001). In clinical and preclinical studies, tibolone has shown beneficial effects in the central nervous system (CNS) (Pinto-Almazan et al., 2017). For example, tibolone showed antidepressant effects in women suffering from depressive symptoms during menopause or post menopause (Kulkarni et al., 2018). However, its effect on cognitive abilities is controversial as while it improved the performance in a test of semantic memory it decreased performance in an executive function task (Fluck et al., 2002). Additionally, in in vitro studies of neuronal or glial cells, as well as in vivo studies using animal models, tibolone has shown to preserve mitochondrial functions, thus attenuating cell death and oxidative damage (Gonzalez-Giraldo et al., 2017). These findings suggest that tibolone might be a promising neuroactive steroid with therapeutic actions for several conditions affecting the CNS. Postmenopausal women have increased susceptibility for developing obesity and chronic inflammation. One hypothesis is that, in women, the hormonal withdrawal during this critical period might account for augmented incidence of inflammatory conditions that may increase the risk of developing CNS pathologies. In this regard, these risk factors could contribute to AD onset in women (Christensen and Pike, 2015). Previous studies have shown increased levels of free fatty acids in the brain of AD patients, suggesting a possible implication of these molecules in the pathogenesis of the disease (Fraser et al., 2010). Indeed, obesity has negative effects on memory and cognition (Smith et al., 2011). Using animal models it has been shown that high levels of free fatty acids induce the expression of peripheral pro-inflammatory cytokines, which can cross the blood-brain barrier and induce metabolic and energy deficits in neurons, astrocytes, and other brain cells (Miller and Spencer, 2014). A growing number of studies have used palmitic acid (PA) in vitro using cells and in vivo in mouse to model the consequences of obesity (Alsabeeh et al., 2018; C. A. Martin-Jimenez et al., 2016). PA is a saturated fatty acid that, in addition to its presence in food, is also present in the cell membranes, where it can be generated by a de novo synthesis mechanism (Carta et al., 2017). Changes in cognition induced by PA have been evidenced in animal models (Contreras et al., 2017). In humans, a high diet in PA induced the activation of the basal ganglia regions including the striatum (Dumas et al., 2016). Although in normal conditions PA plays important physiological roles in cells, it is possible that an imbalance in its concentration can be deleterious for brain functions, thus leading to brain dysfunction (Hussain et al., 2013).