title: Raloxifene and estradiol benzoate both fully restore hippocampal choline acetyltransferase activity in ovariectomized rats.
abstract: Selective estrogen receptor modulators (SERMs) demonstrate tissue-specific estrogen receptor (ER) agonist or antagonist properties. Raloxifene, a prototypical SERM, has ER agonist properties in bone and on cholesterol metabolism but full antagonist properties in the uterus and breast. To characterize the ER agonist/antagonist profile of raloxifene in the brain, we have examined its effect on the activity of a known estrogen-responsive gene product, choline acetyltransferase (ChAT), in the hippocampus and other brain regions of 6-month-old ovariectomized (OVX) Sprague-Dawley rats. Three weeks post-ovariectomy, animals received estradiol benzoate (EB, 0.03 mg or 0.3 mg kg(-1) day(-1) for 3 or 10 days); raloxifene HCl (3.0 mg kg(-1) day(-1) for 3 or 10 days), tamoxifen (3.0 mg kg(-1) day(-1) for 10 days) or vehicle (20% CDX). As previously reported, ChAT activity decreased by approximately 20%-50% in the hippocampus of OVX compared with SHAM-operated control rats with no change in ChAT activity observed in the hypothalamus. Raloxifene or EB reversed the OVX-induced decrease in ChAT activity in the hippocampus but did not change ChAT activity in the hypothalamus. Animals that received combined EB (0.03 mg/kg) plus raloxifene (1 mg/kg) or tamoxifen alone (3.0 or 10 mg/kg) also showed increased hippocampal ChAT activity. Raloxifene failed to increase uterine weight and blocked the estrogen-induced increase in uterine weight, while another SERM, tamoxifen, increased uterine weight. These data demonstrate that raloxifene has estrogen-like properties on hippocampal ChAT activity in vivo, and suggest that benzothiophene SERMs may exert estrogen-like beneficial effects on cholinergic neurotransmission in brain without producing peripheral stimulation of breast or uterine tissue.
authors.affiliation: Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, DC 0530, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.forename: M A
authors.initials: MA
authors.lastname: Glinn
authors.forename: N L
authors.initials: NL
authors.lastname: Ostrowski
authors.forename: Y
authors.initials: Y
authors.lastname: Su
authors.forename: B
authors.initials: B
authors.lastname: Ni
authors.forename: H W
authors.initials: HW
authors.lastname: Cole
authors.forename: H U
authors.initials: HU
authors.lastname: Bryant
authors.forename: S M
authors.initials: SM
authors.lastname: Paul
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D010052:Ovariectomy; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology
chemical_list: D020845:Selective Estrogen Receptor Modulators; C074283:estradiol 3-benzoate; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D002795:Choline O-Acetyltransferase