Abstract
BackgroundRecent work has suggested that the ovarian steroid 17β-estradiol, 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 estrogen have consistently been shown to be protective in vivo, direct protection upon purified neurons is controversial, with many investigators unable to show a direct protection in highly purified primary neuronal cultures. These findings suggest that while direct protection may occur in some instances, an alternative or parallel pathway for protection may exist which could involve another cell type in the brain.Presentation of the HypothesisA hypothetical indirect protective mechanism is proposed whereby physiological levels of estrogen stimulate the release of astrocyte-derived neuroprotective factors, which aid in the protection of neurons from cell death. This hypothesis is attractive as it provides a potential mechanism for protection of estrogen receptor (ER)-negative neurons through an astrocyte intermediate. It is envisioned that the indirect pathway could act in concert with the direct pathway to achieve a more widespread global protection of both ER+ and ER- neurons.Testing the hypothesisWe hypothesize that targeted deletion of estrogen receptors in astrocytes will significantly attenuate the neuroprotective effects of estrogen.Implications of the hypothesisIf true, the hypothesis would significantly advance our understanding of endocrine-glia-neuron interactions. It may also help explain, at least in part, the reported beneficial effects of estrogen in neurodegenerative disorders. Finally, it also sets the stage for potential extension of the hypothetical mechanism to other important estrogen actions in the brain such as neurotropism, neurosecretion, and synaptic plasticity.
Highlights
Recent work has suggested that the ovarian steroid 17β-estradiol, at physiological concentrations, may exert protective effects in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and acute ischemic stroke
In support of a possible neuroprotective role for estrogen, it has been shown that intact adult female rats sustain lower mortality and less neuronal damage as compared to age-matched male rats following middle cerebral artery occlusion [14]
That an ovarian factor is involved in the protection was suggested by the finding that ovariectomy (OVX) eliminates the endogenous protective effect observed in females following cerebral ischemia [14]
Summary
Recent work has suggested that the ovarian steroid 17β-estradiol, at physiological concentrations, may exert protective effects in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and acute ischemic stroke. With respect to the mechanism of action of estrogen protection, several studies have reported that a 24-hour pretreatment with physiological doses of estrogen is necessary to reduce infarct volume following cerebral ischemia in OVX female animals [4,7,16].
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