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

Recent findings in animals emphasize that experimental ischemic brain damage can be strikingly reduced by estrogen; however, the neuroprotective mechanisms 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 amplifying intraischemic cerebral blood flow (CBF). In the present study, the hypothesis that chronic treatment with the pure ER antagonist ICI182,780 (ICI) would increase ischemic brain damage by a blood flow-mediated mechanism was investigated. Adult C57BI/6J mice were pretreated with either subcutaneous ICI (100 μg/day) or oil/ethanol vehicle for 1 week before 2 hours of middle cerebral artery occlusion (MCAO) and 22 hours of reperfusion. Endischemic regional CBF was evaluated in additional cohorts using [¹⁴C]iodoantipyrine autoradiography. Infarction volume as measured by cresyl violet histology was greater in the striatum of ICI-treated females (70±3% of contralateral striatum vs. 40 ±12% in vehicle-treated females). Cortical injury was not enhanced relative to control animals (39 ± 6% of contralateral cortex in ICI group vs. 27 ± 8% in vehicle-treated group). Physiologic variables and ischemic reduction of the ipsilateral cortical laser-Doppler flow signal were similar between groups. Further, ICI treatment did not alter end-ischemic cortical or striatal CBF. The deleterious effect of ICI was limited to females, as there were no differences in stroke damage or CBF between male treatment groups. These data suggest that estrogen inhibits ischemic brain injury in striatum of the female by receptor-mediated mechanisms that are not linked to preservation of intraischemic CBF.