title: The effects of chronic estradiol treatment on working memory deficits induced by combined infusion of beta-amyloid (1-42) and ibotenic acid.
abstract: Estrogen limits in vitro neuron death induced by application of beta-amyloid, the cytotoxic peptide linked to Alzheimer's disease. However, the ability of estrogen to protect neurons and preserve cognitive function in vivo following exposure to beta-amyloid has not been demonstrated. Our objective was to evaluate the potential of estrogen to reduce spatial working memory deficits in female rats induced by administration of a neurotoxic form of beta-amyloid in combination with the excitotoxin, ibotenic acid. The interaction of beta-amyloid with excitotoxic factors may underlie cognitive deficits associated with Alzheimer's disease. Therefore, to create an experimental model typical of early Alzheimer's disease a low dose of ibotenic acid was administered with beta-amyloid into the dorsal hippocampus. Ovariectomized rats were implanted subcutaneously with Silastic capsules that produce physiological levels of 17beta-estradiol 10 days before bilateral intrahippocampal injections of aggregated beta-amyloid (1-42) and ibotenic acid. Capsules remained in situ throughout behavioral testing. When tested 3-10 weeks after neurotoxin treatment, females without estrogen capsules exhibited delay-dependent impairments in working memory performance on a water maze and a radial arm maze. Females treated with estrogen and combined neurotoxins displayed working memory performance comparable to unlesioned females on both tasks. Neurotoxin treatment increased immunoreactivity for glial fibrillary acidic protein but this measure was unaffected by estradiol treatment indicating that estrogen did not limit glial proliferation. Results indicate that estrogen prevented deficits in spatial working memory induced by neurotoxin treatments intended to mimic the pathology of early Alzheimer's disease.
authors.affiliation: Neuroscience Program, Tulane University, New Orleans, LA 70118, USA.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Hruska
authors.forename: Gary P
authors.initials: GP
authors.lastname: Dohanich
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000503:physiopathology*; D016229:Amyloid beta-Peptides; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D007051:Ibotenic Acid; D018782:Maze Learning / Q000502:physiology*; D008569:Memory Disorders / Q000139:chemically induced* / Q000503:physiopathology; D008570:Memory, Short-Term / Q000502:physiology*; D008845:Microinjections; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins; D010052:Ovariectomy; D010446:Peptide Fragments; D051381:Rats; D020318:Rats, Long-Evans; D018709:Statistics, Nonparametric
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D007051:Ibotenic Acid; D004958:Estradiol