Raloxifene and estradiol benzoate both fully restore hippocampal choline acetyltransferase activity in ovariectomized rats |
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Authors: | Wu X Glinn M A Ostrowski N L Su Y Ni B Cole H W Bryant H U Paul S M |
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Institution: | Neuroscience and Endocrine Divisions, Lilly Research Laboratories, Eli Lilly and Company, DC 0530, Lilly Corporate Center, Indianapolis, IN 46285, USA |
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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. |
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Keywords: | Raloxifene Estrogen Choline acetyltransferase activity Hippocampus |
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