From structural biochemistry to expression profiling: neuroprotective activities of estrogen

Estrogens are neuromodulatory and neuroprotective hormones. Chemically, estrogens are steroid compounds and unfold most of their activities through the activation of nuclear receptors that bind to specific target genes and control their transcription. Two subtypes of estrogen receptors are known (estrogen receptor alpha and estrogen receptor beta) and they are expressed throughout the body including the CNS and in particular the brain. We employed large scale DNA-chip-analysis to display the gene expression pattern differentially regulated by both estrogen receptor subtypes in human neuronal cells. We identified different gene families regulated by estrogen receptors that complement the knowledge about the estrogen receptor target genes. Some of these genes may serve neuroprotective functions and may therefore mediate the overall neuroprotective activities of estrogens. In addition to estrogen receptor-dependent neuroprotective effects, estrogen (17beta-estradiol) itself is a compound with a phenolic structure that may display also direct and estrogen receptor-independent antioxidant activities which may be important for the defense against oxidative stress. In summary estrogen can display a wide range of neuroprotective activities through different types of mechanisms and we are only understanding part of the molecular control of these activities which may help to develop neuropreventive strategies against neurodegenerative diseases in the future.