title: Role of nonfeminizing estrogens in brain protection from cerebral ischemia: an animal model of Alzheimer's disease neuropathology.
abstract: Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in in vitro assays using a library of more than 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large, bulky group at the C2 and/or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C, or D rings either reduced or did not markedly change neuroprotection. For this library of compounds, there was a negative correlation between ER binding and neuroprotection, as the more potent compounds showed weaker or no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. Finally, estradiol protected brains from insult-induced Alzheimer's disease (AD) neuropathology, including activation of apoptosis, stimulation of Abeta production, hyperphosphorylation of tau, activation of cyclin-dependent kinases, and activation of catastrophic attempts at neuronal mitosis. Collectively, these results demonstrate that nonfeminizing estrogens are neuroprotective and protect the brain from the induction of AD-like neuropathology in an animal model. These features of nonfeminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, because they are not expected to show the side effects of chronic estrogen therapy that are ER mediated in the liver, uterus, and breast.
authors: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA. jsimpkin@hsc.unt.edu
authors: James W
authors: JW
authors: Simpkins
authors: Yi
authors: Y
authors: Wen
authors: Evelyn
authors: E
authors: Perez
authors: Shaohua
authors: S
authors: Yang
authors: Xiaofei
authors: X
authors: Wang
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D004967:Estrogens / Q000737:chemistry / Q000502:physiology* / Q000627:therapeutic use*; D004970:Estrone / Q000031:analogs & derivatives; D005260:Female; D018696:Neuroprotective Agents; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats
chemical_list: D004967:Estrogens; D018696:Neuroprotective Agents; D004970:Estrone; D004958:Estradiol; D018844:Cyclin-Dependent Kinases