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The Journal of Neuroscience, April 15, 2001, 21(8):2600-2609
Differential Mechanisms of Neuroprotection by 17  -Estradiol in
Apoptotic versus Necrotic Neurodegeneration
Christoph
Harms1,
Marion
Lautenschlager1, 2,
Alexandra
Bergk2,
Juri
Katchanov2,
Dorette
Freyer2,
Krisztian
Kapinya2,
Ulrike
Herwig1,
Dirk
Megow2,
Ulrich
Dirnagl2,
Joerg
R.
Weber2, and
Heide
Hörtnagl1
1 Institute of Pharmacology and Toxicology and
2 Department of Neurology, Medical Faculty Charité,
Humboldt-University at Berlin, D-10098 Berlin, Germany
The major goal of this study was to compare mechanisms of the
neuroprotective potential of 17  -estradiol in two models for oxidative stress-independent apoptotic neuronal cell death with that in
necrotic neuronal cell death in primary neuronal cultures derived from
rat hippocampus, septum, or cortex. Neuronal apoptosis was induced
either by staurosporine or ethylcholine aziridinium (AF64A), as models
for necrotic cell death glutamate exposure or oxygen-glucose
deprivation (OGD) were applied. Long-term (20 hr) pretreatment (0.1 µM 17 -estradiol) was neuroprotective in apoptotic
neuronal cell death induced by AF64A (40 µM) only in hippocampal and septal neuronal cultures and not in cortical cultures. The neuroprotective effect was blocked by the estrogen antagonists ICI
182,780 and tamoxifen and the phosphatidylinositol 3-kinase (PI3-K)
inhibitor LY294002. In glutamate and OGD-induced neuronal damage,
long-term pretreatment was not effective. In contrast, short-term (1 hr) pretreatment with 17 -estradiol in the dose range of 0.5-1.0
µM significantly reduced the release of lactate dehydrogenase and improved morphology of cortical cultures exposed to
glutamate or OGD but was not effective in the AF64A model. Staurosporine-induced apoptosis was not prevented by either long- or
short-term pretreatment. The strong expression of the estrogen receptor- and the modulation of Bcl proteins by 17 -estradiol in
hippocampal and septal but not in cortical cultures indicates that the
prevention of apoptotic, but not of necrotic, neuronal cell death by 17 -estradiol possibly depends on the induction of Bcl proteins and the
density of estrogen receptor-.
Key words:
apoptosis; necrosis; estradiol; AF64A; staurosporine; oxygen-glucose deprivation; Bcl-2; primary neuronal cultures; estrogen
receptor-; hippocampus; cortex; septum; Alzheimer's disease
Copyright © 2001 Society for Neuroscience 0270-6474/01/2182600-10$05.00/0
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