Estrogen receptor antagonist ICI182,780 exacerbates ischemic injury in female mouse

Recent findings in animals emphasize that experimental ischemic brain damag e can be strikingly reduced by estrogen; however, the neuroprotective mecha nisms are not well understood. It was hypothesized that estrogen signaling via cognate estrogen receptors (ERs) within the vasculature is an important aspect of cerebral ischemic protection in the female brain, in part by amp lifying intraischemic cerebral blood flow (CBF). In the present study, the hypothesis that chronic treatment with the pure ER antagonist ICI182,780 (I CI) would increase ischemic brain damage by a blood flow-mediated mechanism was investigated. Adult C57B1/6J mice were pretreated with either subcutan eous ICI (100 mu g/day) or oil/ethanol vehicle for 1 week before 2 hours of middle cerebral artery occlusion (MCAO) and 22 hours of reperfusion. End i schemic regional CBF was evaluated in additional cohorts using [C-14]iodoan tipyrine autoradiography. Infarction volume as measured by cresyl violet hi stology was greater in the striatum of ICI-treated females (70 +/- 3% of co ntralateral striatum vs. 40 +/- 12% in vehicle-treated females). Cortical i njury was not enhanced relative to control animals (39 +/- 6% of contralate ral cortex in ICI group vs. 27 +/- 8% in vehicle-treated group). Physiologi c variables and ischemic reduction of the ipsilateral cortical laser-Dopple r flow signal were similar between groups. Further, ICI treatment did not a lter end-ischemic cortical or striatal CBF. The deleterious effect of ICI w as limited to females, as there were no differences in stroke damage or CBF between male treatment groups. These data suggest that estrogen inhibits i schemic brain injury in striatum of the female by receptor-mediated mechani sms that are not linked to preservation of intraischemic CBF.