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Analysis of the effects of oestrogen receptor alpha (ERalpha)- and ERbeta-selective ligands given in combination to ovariectomized rats.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2008 Apr; Vol. 153 (7), pp. 1432-7. Date of Electronic Publication: 2008 Feb 04. - Publication Year :
- 2008
-
Abstract
- Background and Purpose: Studies with oestrogen receptoralpha (ERalpha)- and ERbeta-selective compounds have already shown that the effects of 17beta-estradiol (E2) on body weight, movement drive and bone-protection are mediated via ERalpha. This study was based on the hypothesis that activation of ERbeta may antagonize ERalpha-mediated effects and designed to investigate potential effects of ERalpha/ERbeta heterodimers.<br />Experimental Approach: Ovariectomized (OVX) female Wistar rats were treated with combinations of the ERalpha-specific agonist 16alpha-LE2 (ALPHA; 1 and 10 microg kg(-1) d(-1)), the ERbeta-specific agonist 8beta-VE2 (BETA; 100 microg kg(-1) d(-1)), the phytoestrogen, genistein (10 mg kg(-1) d(-1)) and with the anti-oestrogen compound, ICI 182,780 (3 mg kg(-1) d(-1)) for three weeks. The combined effects of the substances on body weight increase, tibial bone mineral density (BMD) and the influence on running wheel activity (RWA) were investigated.<br />Key Results: OVX-induced body weight increase was reduced by co-administration of genistein and BETA. Co-application of BETA or genistein with ALPHA had no effect on ALPHA-mediated bone-protection. The RWA of OVX animals was significantly reduced by treatment with genistein but stimulated by application of ALPHA. The stimulatory effect of ALPHA on RWA could be antagonized by co-treatment with the pure antioestrogen ICI 182,780 but also by co-administration of genistein or BETA.<br />Conclusions and Implications: Our results indicate that activation of ERbeta may modulate ERalpha-mediated physiological effects in vivo. The observation that substances with selective affinity for ERbeta are able to antagonize distinct physiological functions, like RWA, may be of great relevance to the pharmaceutical use of such drugs.
- Subjects :
- Animals
Body Weight drug effects
Bone Density drug effects
Dose-Response Relationship, Drug
Drug Therapy, Combination
Estradiol analogs & derivatives
Estradiol pharmacology
Estrogen Antagonists pharmacology
Female
Fulvestrant
Genistein pharmacology
Ligands
Motor Activity drug effects
Ovariectomy
Phytoestrogens pharmacology
Rats
Rats, Wistar
Estrogen Receptor alpha agonists
Estrogen Receptor beta agonists
Estrogens pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 153
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 18246095
- Full Text :
- https://doi.org/10.1038/sj.bjp.0707664