Drugs with estrogen-like potency and brain activity: Potential therapeuticapplication for the CNS

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 t hrough estrogen-mediated mechanisms have been consistently established. Mor eover, studies using in vivo and in vitro models as well as epidemiological data suggest that estrogens provide neuroprotection of central nervous sys tem (CNS) cells implicated in the etiology of neurodegenerative disorders s uch as Alzheimer's (AD) and Parkinson's (PD) diseases. Numerous genomic or non-genomic mechanisms of actions of estrogens in the brain have been docum ented 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. Selec tive estrogen receptor modulators (SERMs) have estrogenic and/or antiestrog enic activity depending on the target tissue. Hence, SERMs have the same be neficial 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. W e will review brain effects of estrogens, steroids possibly acting as pro-d rugs of estrogens such as testosterone and dehydroepiandrosterone (DHEA) an d present novel findings with SERMs. Drugs with estrogen activity in the br ain may have therapeutic potential either by modulating brain neurotransmit ter transmission or through neuroprotective activity.