Estrogen and Stroke

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

“…Note, that even if tamoxifen was acting as a partial ER agonist, it is effective when given acutely up to 3 h after initiation of MCAo, unlike the pretreatment with estrogens which is the only one thought to be due ER-induced synthetic or other long term pathways (Dhandapani and Brann, 2002;Hurn and Brass, 2003). 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.…”

“…Estrogen effects are diverse and include not only actions at estrogen receptors (ER) resulting in changes in bcl-2 gene levels, activation of MAP kinases and/or effects on the cAMP-PKA-CREB pathway (Dhandapani and Brann, 2002;Hurn and Brass, 2003), but also direct effects on [Ca 2+ ] i , inhibition of anion channels and antioxidant activity (Green and Simpkins, 2000). Although the protective actions of estrogens have been observed primarily with chronic treatment as replacement therapy in ovariectomized female rats (Green and Simpkins, 2000;Hurn and Brass, 2003), it has also been shown that higher concentrations of 17β-Estradiol (E2) are neuroprotective in male rats (Toung et al, 1998). Estradiol at high doses was also effective when given up to 3 h, together with a slow-release depot, after permanent MCAo in ovariectomized female rats, and these acute effects were attributed to the antioxidant action of high dose estrogen (Yang et al, 2000).…”

“…Although estrogen is very effective with pretreatments of ∼ 1 week in ovarectomized rats this efficacy has not translated to effectiveness in clinical trials (Hurn and Brass, 2003). Note, that even if tamoxifen was acting as a partial ER agonist, it is effective when given acutely up to 3 h after initiation of MCAo, unlike the pretreatment with estrogens which is the only one thought to be due ER-induced synthetic or other long term pathways (Dhandapani and Brann, 2002;Hurn and Brass, 2003).…”

“…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.…”

Effects of Combined Oral Conjugated Estrogens and Medroxyprogesterone Acetate on Brain Infarction Size after Experimental Stroke in Rat

“…Like estrogen, progesterone has been shown to be protective in models of traumatic brain injury (Bramlett and Dietrich, 2001;Stein, 2001;Wright et al, 2001), but variable effects have been noted after ischemic brain injury (Roof and Hall, 2000;Stein and Hoffman, 2003). Early studies of unopposed estrogen replacement in women report a reduction in risk for cardiovascular disease (Hurn and Brass, 2003). Yet, recent prospective studies of women on prolonged, daily combined hormone replacement therapy (HRT) of conjugated equine estrogens (CEE; 0.625 mg) and medroxyprogesterone acetate (MPA; 2.5 mg) for primary prevention (Rossouw et al, 2002), or on 17b-estradiol alone for secondary stroke prevention (Viscoli et al, 2001), reported no protection or adverse effects of the hormones on women's risk of stroke (Wassertheil-Smoller et al, 2003).…”