Neuroprotection against oxidative stress by estrogens: structure-activity relationship.
Oxidative stress-induced neuronal cell death has been implicated in different neurological disorders and neurodegenerative diseases; one such ailment is Alzheimer's disease. Using the Alzheimer's disease-associated amyloid beta protein, glutamate, hydrogen peroxide, and buthionine sulfoximine, we investigated the neuroprotective potential of estrogen against oxidative stress-induced cell death. We show that 17-beta-estradiol, its nonestrogenic stereoisomer, 17-alpha-estradiol, and some estradiol derivatives can prevent intracellular peroxide accumulation and, ultimately, the degeneration of primary neurons, clonal hippocampal cells, and cells in organotypic hippocampal slices. The neuroprotective antioxidant activity of estrogens is dependent on the presence of the hydroxyl group in the C3 position on the A ring of the steroid molecule but is independent of an activation of estrogen receptors.
Behl
C
C
Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany. chris@mpipsykl.mpg.de
Skutella
T
T
Lezoualc'h
F
F
Post
A
A
Widmann
M
M
Newton
C J
CJ
Holsboer
F
F
D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D000963:Antimetabolites; D000975:Antioxidants; D004967:Estrogens; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; D018698:Glutamic Acid; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide