Neuroprotective effects of an estratriene analog are estrogen receptor independent in vitro and in vivo

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
Brain Research (Impact Factor: 2.84). 04/2005; 1038(2):216-22. DOI: 10.1016/j.brainres.2005.01.026
Source: PubMed


Estrogens are potent neuroprotectants both in vitro and in vivo. In the present study, we compared the potency and efficacy of a non-feminizing estrogen, 2-(1-adamantyl)-4-methylestrone (ZYC-26), with its parent estrogen, estrone, and an expected non-neuroprotective 3-O-methyl analog of (17beta)-2-(1-adamantyl)estradiol (ZYC-23). These estratriene derivatives were tested for their ability to protect in an in vitro lipid peroxidation model, to neuroprotect against oxidative stress in cell culture models, to bind the estrogen receptors (ERalpha and ERbeta), to elicit uterotrophic effects, and to affect brain damage from transient middle cerebral artery occlusion. We observed that in contrast to estrone, neither ZYC-26 nor ZYC-23 bound to either estrogen receptors (ER) and both failed to elicit a uterotrophic response. In vitro, the active estrogen analogue ZYC-26 was more potent that estrogen in its ability to inhibit lipid peroxidation and to protect HT-22 cells from either glutamate or iodoacetic acid (IAA) toxicity. Further, ZYC-26 was as active in preventing brain damage from transient middle cerebral artery occlusion (MCAO) as was estrone. Collectively, these studies suggest that the antioxidant activity, rather than ER binding of non-feminizing estrogens such as ZYC-26, mediates their potent neuroprotective activity. Further, in view of the now known toxicities of chronic feminizing estrogen use in older women, non-feminizing estrogens may be a useful alternative for estrogen-induced brain protection.

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    • "● 17-a-estradiol (EST) is considered to be a nonfeminizing estrogen with reduced affinity for estrogen receptors. This estrogen is neuroprotective against ischemia in animal models, as well as in vitro (Perez et al., 2005). It also protects against neurodegenerative effects in cell and animal models of Parkinson's disease (Dykens et al., 2005) and cerebrovascular disease (Liu et al., 2005). "
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    ABSTRACT: Four agents - acarbose (ACA), 17-α-estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB) - were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. NDGA increased male median lifespan by 8-10% at three different doses, with P-values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late-life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.
    Full-text · Article · Oct 2013 · Aging cell
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    • "Instead, the in vitro neuroprotective efficacy of these compounds appears to rely on bulky side groups and their redox potential (Yi et al., 2011). In vitro screening against several apoptotic insults successfully identified several such compounds that were similarly neuroprotective in ovariectomized rats undergoing tMCAO (Liu et al., 2002; Perez et al., 2005). These compounds appear to act by blocking lipid peroxidation through intercalation into the cell membrane and redox recycling through the mitochondria (Simpkins and Dykens, 2008). "
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    ABSTRACT: Estrogens, particularly 17β-estradiol (E2), are powerful neuroprotective agents in animal models of cerebral ischemia. Loss of endogenous E2 in women at menopause or after surgical oopherectomy leads to an increase risk of stroke, neurodegenerative disease, and cognitive decline. However, several clinical trials found detrimental effects of E2 therapy after menopause, including increased stroke risk and dementia. Recent animal and human studies now support the "critical period" hypothesis for E2 neuroprotection whereby E2 therapy must begin soon after the loss of endogenous E2 production to have a beneficial effect. Although a wide array of mechanisms has been proposed for estradiol (E2)-dependent neuroprotection in cerebral ischemia and neurodegenerative disease, most of these mechanisms involve interactions of E2 with one of its cognate receptors, estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), or the G protein-coupled estrogen receptor (GPER). However, these receptors are not uniformly distributed throughout the brain, across different cell types, and within cellular compartments. Such differences likely play a role in the ability of E2 and ER selective ligands to protect the brain from ischemia. This review examines the changes in ER expression and location that may underlie the loss of E2 neuroprotection seen with aging and long-term estrogen deprivation (LTED). Recent results suggest that the loss of ERα that accompanies aging and LTED plays an important role in the loss of E2-dependent neuroprotection.
    Full-text · Article · Mar 2013 · Brain research
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    • "Subcutaneously implantation of αE2 24 hours before MCA occlusion showed neuroprotective effects. The survival rate of vehicle-treated animals was 54%, whereas the survival rate of αE2-treated animals was 71% (Simpkins et al., 1997b), even though αE2 binds to ER-isoforms with an approximately 40-fold lower affinity (Perez et al., 2005a). Vehicle-treated rats showed the expected ischemic lesion; with the maximum ischemic area (24.1 ± 2.4%) occurring in the slice obtained 9 mm posterior to the olfactory bulb and a smaller lesion occurring in slices obtained from more rostral and more caudal areas. "
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    ABSTRACT: Menopause is associated with a precipitous decline in circulating estrogens and a resulting loss of the neuroprotective actions of this steroid hormone. In view of the results of the Women's Health Initiative and the preceding knowledge that orally administered estrogens has a variety of adverse side effects, likely through actions on peripheral estrogen receptor alpha (ERα), we initiated a program of research to synthesis and assess a group of non-feminizing estrogens that lack ability to interact with ERs but retain much of the neuroprotective action of feminizing estrogens. This program of research is aimed at the identification of compounds which do not stimulate ERs but are potentially neuroprotective in vitro and in animal models of neuronal cell death. We discovered that the most effective non-feminizing estrogens were those with large bulky groups in the 2 and/or 4 carbon of the phenolic A ring of the steroid. These compounds were 8- to 114-fold more potent than 17 β-estradiol (βE2), but lacked ER binding capacity in vitro and feminizing effects in vivo. The success of this program of research suggests that strategies to optimize non-feminizing estrogens for use in postmenopausal women can be successful.
    Full-text · Article · Nov 2010 · Brain research
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