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Estrogen and raloxifene activities on amyloid-beta-induced inflammatory reaction.

Thomas T, Bryant M, Clark L, Garces A, Rhodin J.

Department of Anatomy, University of South Florida, Tampa, Florida 33612, USA.

The prevalence of Alzheimer's disease (AD) in women is double that of men. Several studies indicate that use of estrogen after menopause by women may reduce the risk of developing AD. The risk of estrogen-dependent tumors associated with estrogen replacement therapy has prompted the use of alternatives, like the SERM raloxifene, which exert estrogen agonist effects on selected target tissues. Whether SERMS provide cognitive and cardiovascular benefits comparable to those of estrogens is an active area of investigation in women's health. A chronic inflammatory process is central to the pathology of Alzheimer's disease. Using an animal model we compared the anti-inflammatory activity of orally administered estrogens (2 mg/kg) and raloxifene (3 mg/kg) in ovariectomized rats. Morphological analysis of Abeta(1-40)-induced inflammatory reaction featured adhesion and transmigration of leukocytes across the vessel wall, endothelial disruption, and platelet activation. Estrogen showed remarkable anti-inflammatory action, whereas raloxifene had no significant beneficial effect. Inhibition of the inflammatory process may contribute to the reported efficacy of estrogen in the treatment of AD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11162193&dopt=Abstract raloxifene Evista



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Selective estrogen receptor modulators: the ideal estrogen replacement?(2)(2).

Sexton MJ, Gherman RB.

Department of OB/GYN, Division of Maternal/Fetal Medicine, Portsmouth Naval Hospital, Portsmouth, Virginia, USA

The ultimate estrogen for replacement therapy should exert beneficial actions upon the skeletal, cardiovascular, and central nervous systems while displaying minimal side effects in the uterus and breast. Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, have recently been studied to achieve these aims. Not only are these agents potentially effective in reducing a patient's risk of breast carcinoma but they have also been shown to increase bone mineral density and prevent osteoporosis. Displaying favorable effects on lipid metabolism, SERMs also may be protective against coronary heart disease and myocardial infarction. Tamoxifen's adverse side effects on the uterus have not been noted with raloxifene, because the latter behaves as an estrogen antagonist in the endometrium. Ongoing studies, such as the Study of Tamoxifen and Raloxifene and the Raloxifene Use for the Heart trials, may help to further determine whether SERMs are the ideal estrogen for the postmenopausal female patient.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11164349&dopt=Abstract raloxifene Evista



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Estrogenic activity of tamoxifen and raloxifene on rat brain AMPA receptors.

Cyr M, Morissette M, Landry M, Di Paolo T.

Oncology and Molecular Endocrinology Research Center, Laval University Medical Center and Faculty of Pharmacy, Laval University Quebec, Sainte-Foy, Canada.

We have previously shown in rats that estradiol has brain regionally specific effects on AMPA receptors. The present study investigated hormonal specificity of AMPA receptors by comparing the effect of estradiol with tamoxifen or raloxifene, which have varying effects on estrogen response in breast, bone and uterus. Ovariectomy in rats decreased uterus weight which was restored by estradiol treatment, whereas tamoxifen and raloxifene had only a weak effect. Ovariectomy left unchanged AMPA receptor specific binding in rat brain whereas estradiol, tamoxifen and raloxifene decreased it in cortical and striatal regions of ovariectomized rats. Hence, tamoxifen and raloxifene showed agonist estrogenic activity on AMPA receptors in specific brain regions, which can be dissociated from their antagonist estrogenic activity in the periphery.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11234759&dopt=Abstract raloxifene Evista



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Effect of tibolone and raloxifene on the tail temperature of oestrogen-deficient rats.

Berendsen HH, Weekers AH, Kloosterboer HJ.

Pharmacology Department, NV Organon, P.O. Box 20, 5340 BH, Oss, Netherlands. H.Berendsen organon.oss.akzonobel.nl

Oestradiol, clonidine, tibolone and raloxifene were tested for their effects on the tail temperature of oestrogen deficient rats, a potential new model that can be used to test compounds that may be of use in the treatment of hot flushes in humans. Rats underwent ovariectomies or sham operations and their tail temperature and physical activity were measured telemetrically. Oestrogen depletion affected tail temperature in the rats' active, but not their resting phase. During the transition from the resting to the active phase, tail temperature in normal rats dropped by about 6 degrees C, but only by approximately 1 degrees C after ovariectomy. Treatment of the ovariectomised rats with oestrogen, clonidine or tibolone dose-dependently restored the drop in tail temperature. However, raloxifene did not change the tail temperature of ovariectomised rats. Thus, tibolone and raloxifene have different effects on the temperature regulation in the tail. This method of measuring tail temperature free of stress in ovariectomised rats may serve as a useful procedure for selecting compounds that are of potential use in the treatment of hot flushes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11348629&dopt=Abstract raloxifene Evista



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Oestrogenic effects of neonatal administration of raloxifene on hypothalamic-pituitary-gonadal axis in male and female rats.

Pinilla L, Gonzalez LC, Gaytan F, Tena-Sempere M, Aguilar E.

Department of Physiology, Faculty of Medicine, University of Cordoba, Avda. Menendez Pidal s/n, 14004 Cordoba, Spain. fi1agbee lucano.uco.es

Selective oestrogen receptor modulators constitute a family of drugs that are used increasingly in the management of oestrogen-associated pathology. Raloxifene is a selective oestrogen receptor modulator that is used to treat and prevent osteoporosis in post-menopausal women. The actions of raloxifene on bone, breast, uterus and serum cholesterol concentrations have been widely analysed, but very few studies have investigated the possible actions of this drug on the central nervous system. The central nervous system of the newborn rat is very sensitive to oestrogen action. In this study a series of experiments was conducted to analyse the effects of different doses of raloxifene (50, 100, 250 or 500 microg per rat per day) administered to neonatal rats on days 1-5 of age. Female rats treated with raloxifene showed decreased gonadotrophin secretion, hyperprolactinaemia, advanced vaginal opening, decreased body weight, persistent presence of cornified epithelial cells in vaginal smears, anovulation, inhibition of positive feedback between oestradiol and LH, and infertility. Male rats showed delayed balanopreputial separation, reduced body weight and hyperprolactinaemia. All these changes resemble those obtained after neonatal administration of oestradiol benzoate, thus indicating, for the first time, that raloxifene exerts an oestrogenic action on the hypothalamic-pituitary structures controlling reproductive function in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11373178&dopt=Abstract raloxifene Evista



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Neuroprotective properties of 17beta-estradiol, progesterone, and raloxifene in MPTP C57Bl/6 mice.

Callier S, Morissette M, Grandbois M, Pelaprat D, Di Paolo T.

Oncology and Molecular Endocrinology Research Center, and Faculty of Pharmacy, Laval University, Quebec, Qc, G1K 7P4, Canada.

Previous work from our laboratory showed prevention of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induced dopamine depletion in striatum of C57Bl/6 mice by 17beta-estradiol, progesterone, and raloxifene, whereas 17alpha-estradiol had no effect. The present study investigated the mechanism by which these compounds exert their neuroprotective activity. The hormonal effect on the dopamine transporter (DAT) was examined to probe the integrity of dopamine neurons and glutamate receptors in order to find a possible excitotoxic mechanism. Drugs were injected daily for 5 days before MPTP (four injections, 15 mg/kg ip at 2-h intervals) and drug treatment continued for 5 more days. MPTP induced a decrease of striatal DAT-specific binding (50% of control) and DAT mRNA in the substantia nigra (20% of control), suggesting that loss of neuronal nerve terminals was more extensive than cell bodies. This MPTP-induced decrease of striatal [(125)I]RTI-121 specific binding was prevented by 17beta-estradiol (2 microg/day), progesterone (2 microg/day), or raloxifene (5 mg/kg/day) but not by 17alpha-estradiol (2 microg/day) or raloxifene (1 mg/kg/day). No treatment completely reversed the decreased levels of DAT mRNA in the substantia nigra. Striatal [(125)I]RTI-121 specific binding was positively correlated with dopamine concentrations in intact, saline, or hormone-treated MPTP mice. Striatal NMDA-sensitive [(3)H]glutamate or [(3)H]AMPA specific binding remained unchanged in intact, saline, or hormone-treated MPTP mice, suggesting the unlikely implication of changes of glutamate receptors in an excitotoxic mechanism. These results show a stereospecific neuroprotection by 17beta-estradiol of MPTP neurotoxicity, which is also observed with progesterone or raloxifene treatment. The present paradigm modeled early DA nerve cell damage and was responsive to hormones.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11400179&dopt=Abstract raloxifene Evista