Drugs with Estrogen-like Potency and Brain Activity Potential Therapeutic Application for the CNS

Abstract

Numerous reports, ranging from molecular investigations to clinical studies, demonstrate the potency of estrogens to modulate brain function and their implications in schizophrenia and depression. Alterations of dopaminergic, cholinergic, GABAergic, glutamatergic and serotonergic neurotransmission through estrogen-mediated mechanisms have been consistently established. Moreover, studies using in vivo and in vitro models as well as epidemiological data suggest that estrogens provide neuroprotection of central nervous system (CNS) cells implicated in the etiology of neurodegenerative disorders such as Alzheimer s (AD) and Parkinson s (PD) diseases. Numerous genomic or non-genomic mechanisms of actions of estrogens in the brain have been documented implicating classical nuclear estrogen receptors as well as possible estrogen membrane receptors, antioxidant activity of steroids, their effect on fluidity as well as on antiapoptotic proteins and growth factors. Selective estrogen receptor modulators (SERMs) have estrogenic and/or antiestrogenic activity depending on the target tissue. Hence, SERMs have the same beneficial effect as estrogen in skeleton and cardiovascular systems but act as antagonists in breast and uterus. The finding of beneficial side effects of SERMs in the CNS might improve their risk-benefit ratio in traditional indications. In this review, we will survey schizophrenia and depression as examples of mental diseases and AD and PD as neurodegenerative diseases. We will review brain effects of estrogens, steroids possibly acting as pro-drugs of estrogens such as testosterone and dehydroepiandrosterone (DHEA) and present novel findings with SERMs. Drugs with estrogen activity in the brain may have therapeutic potential either by modulating brain neurotransmitter transmission or through neuroprotective activity.

Antidepressant-Like Effect of Different Estrogenic Compounds in the Forced Swimming Test

“…In general, the biological actions of estrogens can be mediated through a rapid nongenomic and a delayed genomic mechanism (Cyr et al, 2000;McEwen, 1991McEwen, , 1999Wehling, 1997;Wise et al, 2001). The first mechanism is mediated by membrane receptors and second messengers (Cyr et al, 2000;McEwen et al, 2001;Nadal et al, 2000).…”

“…The first mechanism is mediated by membrane receptors and second messengers (Cyr et al, 2000;McEwen et al, 2001;Nadal et al, 2000). The other mechanism involves the interaction with intracellular receptors that implies the activation of transcription factors (McEwen, 1991;McEwen et al, 2001).…”

“…Later, this increased availability promotes adaptive changes on specific receptor systems, as it has been shown for the 5-HT 1A , 5-HT 2A/C and for the noradrenergic a 2 and b receptor subtypes (Blier, 2001;Blier and Montigny, 1994;Chaput et al, 1991;Dawson and Nguyen, 1998;Duman, 1999;Gobert and Millan, 1999;Le Poul et al, 2000;Stahl, 1998a). On the other hand, in vitro studies demonstrate that estrogens can interact, at several levels, with the dopaminergic, the noradrenergic, and the serotonergic systems (Attali et al, 1997;Bethea et al, 1998;Biegon et al, 1983;Cyr et al, 2000;McEwen, 1999;Rubinow et al, 1998). For example, estrogens can inhibit the function of the monoaminergic transporter (Ghraf et al, 1983;Michel et al, 1987;Wilson et al, 1988) and interact with either 5-HT 1A , 5-HT 2A , or b-adrenergic receptors in several brain areas (Biegon et al, 1983;Fink et al, 1996;Kendall et al, 1982;Mize and Alper, 2000;Ö sterlund et al, 1999;Raap et al, 2000;Sumner and Fink, 1995).…”

Insights into Rapid Modulation of Neuroplasticity by Brain Estrogens

“…Owing to the neuroprotective and neurotrophic effects of 17b-estradiol it is not surprising that its use as an adjunct treatment in a number of disorders has been investigated. Results for a limited number of clinical studies have indicated a potential beneficial role of estrogens in disorders such as schizophrenia (Cyr et al, 2000;Kulkarni et al, 2008;Hughes et al, 2009;Kulkarni, 2009;Sanchez et al, 2010b). However, it must be noted that longterm treatments of women aged 65 years with conjugated equine estradiol and medroxyprogesterone showed no beneficial effect of this treatment in protection against cognitive decline.…”

Breast Cancer, Estrogen Receptor and Ligands

“…Moreover the non-genomic effect of steroids could be attributed to their binding with the sex-hormon-binding globulin (SHBG) receptor, that is a G-protein-coupled receptor (GPCR), located at the membrane and has been functionally identified in a number of tissues such as prostate, testis, liver, and breast [78,79]. Finally, the rapid steroid action could potentially be induced in the absence of a receptor, by influencing membrane fluidity [80,81].…”