Neuroprotective actions of selective estrogen receptor modulators

Abstract

Decreasing levels of sex hormones with aging may have a negative impact on brain function, since this decrease is associated with the progression of neurodegenerative disorders, increased depressive symptoms and other psychological disturbances. Extensive evidence from animal studies indicates that sex steroids, in particular estradiol, are neuroprotective. However, the potential benefits of estradiol therapy for the brain are counterbalanced by negative, life-threatening risks in the periphery. A potential therapeutic alternative to promote neuroprotection is the use of selective estrogen receptor modulators (SERMs), which may be designed to act with tissue selectivity as estrogen receptor agonists in the brain and not in other organs. Currently available SERMs act not only with tissue selectivity, but also with cellular selectivity within the brain and differentially modulate the activation of microglia, astroglia and neurons. Finally, SERMs may promote the interaction of estrogen receptors with the neuroprotective signaling of growth factors, such as the phosphatidylinositol 3-kinase/glycogen synthase kinase 3 pathway.

Figures

Fig. 1

Estrogenic compounds can bind the intracellular estrogen receptors (ERα and ERβ) which are then translocated to the cell nucleus (1). There they recognize specific estrogen response elements (ERE), recruit additional cofactors and modulate gene expression. Alternatively, estrogen receptors (ERs) can interact with other transcription factors (TF), regulating the expression of genes with different response elements (RE). Estrogen receptors can also be phosphorylated by receptor tyrosine kinases (RTK) (2); this phosphorylation affects the receptor activity, which can be activated and translocated to the nucleus even in the absence of ligand. On the other hand, both cytosolic and membrane bound estrogen receptors can transactivate receptor tyrosine kinases or receptor associated kinases, modulating intracellular cascades. Membrane estrogen receptors (mbER) are variants of intracellular receptors, that can be attached to the plasma membrane, where directly interact with signaling molecules (3) like PI3K, activating PI3K and MAPKs pathways, or with other receptors, such as metabotropic glutamate receptors (mGluR1) (4). Estrogens and derivatives can also bind G-protein coupled receptors (GPCR) (5). All these signals through plasma membrane activate intracellular cascades that end in cytosol targets and transcription factors and cofactors that modulate gene expression. Finally, estrogenic compounds can find receptors in specific organelles, such as mitochondria (6) or in very specialized cellular structures, such as synapses, or can buffer free radicals due to their anti-oxidant properties (7).