Role of astrocytes in estrogen-mediated neuroprotection

Recent work has suggested that the ovarian steroid hormone, 17β-estradiol (E2), at physiological concentrations, may exert protective effects in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and acute ischemic stroke. While physiological concentrations of E2 have consistently been shown to be protective in vivo, direct protection of neurons remains controversial, suggesting that while direct protection of neurons may occur in some instances, an alternative or parallel pathway for protection may exist which could involve another cell type in the brain. In the present review, we summarize the data in support of a possible role for astrocytes in the mediation of neuroprotection by E2. We also summarize the data suggesting a non-classical estrogen receptor may underlie some of the protective effects of E2 by activating cellular signaling pathways, such as extracellular-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt. A possible indirect pathway involving astrocytes may act in concert with the proposed direct pathway to achieve a widespread, global protection of both ER positive and negative neurons.