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Inhibition of brain oestrogen receptors by RU 58668
1Department of Cell Biology and Anatomy, Mount Sinai School of Medicine, City University of New York, NY 10029, USA.
Abstract:
The purpose of this study was to determine if injections of the 11 beta-substituted steroidal antioestrogen, RU 58668, would block two measures of oestrogen receptor action in ovariectomized adult female rats. Using an in vitro nuclear exchange assay, it was found that RU 58668 reduced cell nuclear [3H]-oestradiol binding in brain tissue 24 h after it was injected. However, pituitary cell nuclear [3H]-oestradiol binding was significantly reduced just 2 h after the antioestrogen was injected. Our results demonstrate that RU 58668 can reach the brain following a subcutaneous injection, but that it needs more time to reach the brain than it does to reach the pituitary. Since the levels of hypothalamic and pituitary progestin receptors are known to be regulated by oestradiol, cytosolic [3H]-R5020 binding was used as an in vitro assay of endogenous oestrogen receptor action. RU 58668 blocked induction by oestradiol of cytosolic [3H]-R5020 binding in both the brain and pituitary 48 h after it was injected. In the absence of oestradiol, RU 58668 did not stimulate cell nuclear [3H]-oestradiol binding or cytosolic [3H]-R5020 binding in either brain or pituitary. In conclusion, injections of RU 58668 blocked two measures of oestrogen receptor action in the brain and pituitary without showing oestrogenic activity itself.
Insights
The steroidal antioestrogen RU 58668 effectively blocks oestrogen receptor action in rat brain and pituitary tissues. This compound demonstrates anti-oestrogenic effects without exhibiting oestrogenic activity itself.
Area of Science:
- Endocrinology
- Neuroendocrinology
- Pharmacology
Background:
- Oestrogen receptors play a critical role in regulating various physiological processes in the brain and pituitary.
- Understanding the action of antioestrogens is crucial for developing targeted therapies for hormone-dependent conditions.
Purpose of the Study:
- To investigate the efficacy of the 11 beta-substituted steroidal antioestrogen, RU 58668, in blocking oestrogen receptor action.
- To assess the time-dependent distribution and effects of RU 58668 in the brain and pituitary of ovariectomized rats.
Main Methods:
- In vitro nuclear exchange assay to measure [3H]-oestradiol binding in brain and pituitary tissues.
- Cytosolic [3H]-R5020 binding assay to evaluate endogenous oestrogen receptor action by assessing progestin receptor induction.
- Subcutaneous injection of RU 58668 in ovariectomized adult female rats.
Main Results:
- RU 58668 reduced pituitary cell nuclear [3H]-oestradiol binding within 2 hours and brain tissue binding within 24 hours, indicating differential tissue distribution.
- RU 58668 blocked oestradiol-induced cytosolic [3H]-R5020 binding in both brain and pituitary 48 hours post-injection.
- RU 58668 did not exhibit oestrogenic activity, as it did not stimulate nuclear oestradiol or progestin receptor binding in the absence of oestradiol.
Conclusions:
- RU 58668 effectively reaches both brain and pituitary tissues after subcutaneous administration.
- The antioestrogen RU 58668 acts as a pure anti-oestrogen, blocking oestrogen receptor-mediated effects in the central nervous system and pituitary.
- RU 58668 shows potential as a therapeutic agent for conditions involving oestrogen receptor signalling.
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