Differential mechanisms of neuroprotection by 17 beta-estradiol in apoptotic versus necrotic neurodegeneration.
The major goal of this study was to compare mechanisms of the neuroprotective potential of 17 beta-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 microm 17 beta-estradiol) was neuroprotective in apoptotic neuronal cell death induced by AF64A (40 microm) 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 beta-estradiol in the dose range of 0.5-1.0 microm 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-alpha and the modulation of Bcl proteins by 17 beta-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 beta-estradiol possibly depends on the induction of Bcl proteins and the density of estrogen receptor-alpha.
Harms
C
C
Institute of Pharmacology and Toxicology and Department of Neurology, Medical Faculty Charité, Humboldt-University at Berlin, D-10098 Berlin, Germany.
Lautenschlager
M
M
Bergk
A
A
Katchanov
J
J
Freyer
D
D
Kapinya
K
K
Herwig
U
U
Megow
D
D
Dirnagl
U
U
Weber
J R
JR
Hörtnagl
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001388:Aziridines / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D005947:Glucose / Q000172:deficiency / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009336:Necrosis; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000378:metabolism; D020665:Septum of Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors
D001388:Aziridines; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D018696:Neuroprotective Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D018698:Glutamic Acid; D004958:Estradiol; C044894:ethylcholine aziridinium; D007770:L-Lactate Dehydrogenase; D019311:Staurosporine; D005947:Glucose; D002794:Choline