ICI 182,780: a pure antiestrogen that affects behaviors and energy balance in rats without acting in the brain

Abstract

ICI 182,780 is one of a new class of steroidal antiestrogens that differs from nonsteroidal antiestrogens, such as tamoxifen, in a number of respects. 1) It is bound by estrogen receptors with a high affinity, similar to that for estradiol. 2) It is a "pure" antiestrogen in that it does not mimic any of the effects of estradiol. 3) This class of antiestrogens does not seem to be bound by antiestrogen binding sites. 4) ICI 182,780 may not be active in the brain after peripheral administration. Indeed, ICI 182,780 blocked in vivo cell nuclear binding of [3H]estradiol in uterus, pituitary, and adipose tissue but not in hypothalamus-preoptic area. In vitro, ICI 182,780 competed for binding by neural estrogen receptors with an affinity comparable with that for estradiol. When given to ovariectomized rats, ICI 182,780 did not mimic any of the actions of estradiol. Instead, ICI 182,780 treatment completely blocked the uterotrophic effects of estradiol and attenuated the actions of estradiol on linear growth, carcass fat content, fat pad weight, and sexual receptivity. Treatment with ICI 182,780 also attenuated the estrogenic effects of tamoxifen on food intake, body weight and composition, linear growth, and uterine weight. These findings support the concept that, in addition to its actions in the brain, estradiol can act peripherally to modulate regulatory behaviors, energy balance, and estrous behavior. They are also consistent with the hypothesis that nonsteroidal antiestrogens, such as tamoxifen, affect energy balance via estrogen receptors, rather than antiestrogen binding sites.

Neuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity

“…No other times were studied. Tamoxifen has an IC 50 for displacement of 3 H estradiol of ∼1uM in the brain (Wade et al, 1993). This is similar to its effectiveness as an antioxidant as shown in Fig.…”

“…In the present study we tested whether the neuroprotective effect of tamoxifen is maintained by tamoxifen when ICI 182,780, a pure ER antagonist, was coadministered. Since ICI 182,780 has been shown not to penetrate the BBB ( Wade et al, 1993), we administered it intravaneously and intracisternally, thus testing whether tamoxifen induced neuroprotection involves an action on either peripheral or central estrogen receptors (Hurn and Brass, 2003). In this case we gave tamoxifen at the time of the occlusion and ICI 182,780 just prior to tamoxifen, since we assume that there is no time-dependent change in mechanism as the amount of protection is the same within this time window (Kimelberg et al, 2000(Kimelberg et al, ,2003.…”

“…We used a single dose of ICI 182,780 to conserve animals and the dose used was based on the data in the paper by Wade et al (1993), which also showed that the brain is inaccessible to ICI 182,780 which was the reason we used intracisternal as well as intravenous injection. In that paper the ICI compound was shown to have a 2,300 fold higher affinity than tamoxifen for displacing 3 H estradiol binding to brain tissue with an EC50 of ∼10 −10 M. Based on a rat total brain weight of 2mg (since estradiol enters cells) and that ICI does not leave the brain readily since it doesn't get in, our dose of 10 ug gives an average concentration of 8.2 uM (10 −5 g/607 (MW)×0.002L) in the brain.…”

“…at ischemia as it rapidly enters the brain, and the single i.v. dose of ICI 182,780 we used was ∼330 ug compared to Wade et al, (1993) of 250 ug/day. No other times were studied.…”

Similarities and distinctions in the mode of action of different classes of antioestrogens.

“…The central effects of ICI 182780 and EM-800 also differ significantly and this difference could have profound implications for tolerance and for potential utility in younger women. At doses which provide efficacy on peripheral tissues, ICI 182780 does not enter the brain (Wade et al 1993, Ordog et al 1998) and thus would not be expected to exacerbate or precipitate hot flushes or to affect adversely neurone function (mood control, neurodegenerative conditions etc), or to disturb the hypothalamic-pituitary-ovarian axis. The limited clinical data available to date support this assumption (Thomas et al 1994, Howell et al 1995.…”