title: Periodic 17β-estradiol pretreatment protects rat brain from cerebral ischemic damage via estrogen receptor-β.
abstract: Although chronic 17β-estradiol (E2) has been shown to be a cognition-preserving and neuroprotective agent in animal brain injury models, concern regarding its safety was raised by the failed translation of this phenomenon to the clinic. Previously, we demonstrated that a single bolus of E2 48 hr prior to ischemia protected the hippocampus from damage in ovariectomized rats via phosphorylation of cyclic-AMP response element binding protein, which requires activation of estrogen receptor subtype beta (ER-β). The current study tests the hypothesis that long-term periodic E2-treatment improves cognition and reduces post-ischemic hippocampal injury by means of ER-β activation. Ovariectomized rats were given ten injections of E2 at 48 hr intervals for 21 days. Hippocampal-dependent learning, memory and ischemic neuronal loss were monitored. Results demonstrated that periodic E2 treatments improved spatial learning, memory and ischemic neuronal survival in ovariectomized rats. Additionally, periodic ER-β agonist treatments every 48 hr improved post-ischemic cognition. Silencing of hippocampal ER-β attenuated E2-mediated ischemic protection suggesting that ER-β plays a key role in mediating the beneficial effects of periodic E2 treatments. This study emphasizes the need to investigate a periodic estrogen replacement regimen to reduce cognitive decline and cerebral ischemia incidents/impact in post-menopausal women.
authors.affiliation: Cerebral Vascular Disease Research Laboratories, Department of Neurology, University of Miami, Miami, Florida, USA. ARaval@med.miami.edu
authors.forename: Ami P
authors.initials: AP
authors.lastname: Raval
authors.forename: Raquel
authors.initials: R
authors.lastname: Borges-Garcia
authors.forename: William
authors.initials: W
authors.lastname: Javier Moreno
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Perez-Pinzon
authors.forename: Helen
authors.initials: H
authors.lastname: Bramlett
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D008568:Memory / Q000187:drug effects; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010052:Ovariectomy; D010100:Oxygen / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D047629:Estrogen Receptor beta; D018696:Neuroprotective Agents; D004958:Estradiol; D005947:Glucose; D010100:Oxygen