Role of nonfeminizing estrogens in brain protection from cerebral ischemia: An animal model of Alzheimer's disease neuropathology

James W. Simpkins, Yi Wen, Evelyn Perez, Shaohua Yang, Xiaofei Wang

Research output: Contribution to journalArticle

38 Scopus citations

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, balky 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 Aβ 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.

Original languageEnglish
Pages (from-to)233-242
Number of pages10
JournalAnnals of the New York Academy of Sciences
Volume1052
DOIs
StatePublished - 1 Jan 2005

Keywords

  • Alzheimer's disease
  • Estrogens
  • Neuroffibrillary tangles
  • Neuroprotection
  • Stroke

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