Estrogen-astrocyte interactions: implications for neuroprotection.
BACKGROUND
Recent work has suggested that the ovarian steroid 17beta-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.


OBJECTIVE
A 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.


METHODS
We hypothesize that targeted deletion of estrogen receptors in astrocytes will significantly attenuate the neuroprotective effects of estrogen.


CONCLUSIONS
If 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.
Dhandapani
Krishnan M
KM
Institute of Molecular Medicine and Genetics, Neurobiology Program and Department of Neurology, 1120 15th Street, Medical College of Georgia, Augusta, GA 30912, USA. mp5403gs@mail.mcg.edu
Brann
Darrell W
DW
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D002545:Brain Ischemia / Q000188:drug therapy; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D008962:Models, Theoretical; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000172:deficiency / Q000378:metabolism; D012377:Rodentia; D015398:Signal Transduction / Q000502:physiology
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D004958:Estradiol