Mechanisms of neuroprotection by estrogen and selective estrogen receptor modulators

Menopause is a natural event in the process of aging, which is characterized by the cessation of monthly reproductive cycles, due to a depletion of the ovarian steroid, 17β-estradiol (17β-E₂). To offset many of the problems associated with postmenopausal 17β-E₂ deficiency, hormone replacement therapy (HRT) is currently in widespread clinical use. However, there is concern that HRT may increase the risk for breast and uterine cancers due to 17β-E₂ effects on these tissues. This caveat/limitation has spurred the search for so-called “selective estrogen receptor modulators (SERMs)”, such as tamoxifen, which provide the beneficial effects of 17β-E₂ without many of its undesirable side effects.; Recent work has suggested a neuroprotective role for both 17β-E ₂ and SERMs in animal models of brain injury, although the mechanism of action for these compounds is not clear. To address this issue, the present studies sought to elucidate the neuroprotective mechanisms of 17β-E ₂ and tamoxifen utilizing cell culture models of neuronal function as well as utilizing microarray technology. 17β-E₂ and tamoxifen failed to protect pure neuronal cerebrocortical cultures from a variety of cell death paradigms, however a protective effect was observed when neurons were co-cultured in the presence of glial cells (astrocytes), suggesting an estrogen regulated, astrocyte-derived factor may protect neurons from cell death. Further work identified the astrocyte-derived to be TGF-β, which was important for both the basal survival of neurons, as well as the protection of neurons following injury. The protection elicited by astrocyte-derived TGF-β appears to be mediated, at least in part, by the TGF-β Type II receptor, which leads to activation of the MKK4-JNK-c-Jun-AP-1 signaling pathway. A role for astrocyte-derived TGF-β in mediating the neuroprotective effect of 17β-E₂ and tamoxifen was further suggested by the ability of both compounds to significantly stimulate the release of both TGF-β1 and TGF-β2 from cultured rat cortical astrocytes. Astrocytes were demonstrated to possess both known estrogen receptors, ER-α and ER-β, as assessed by RT-PCR and Western blotting, further suggesting astrocytes may represent novel targets for estrogen action in the brain. (Abstract shortened by UMI.)...