LY353381.HCl, a selective estrogen receptor modulator, and experimental stroke

Background and Purpose-The impact of postmenopausal estrogen replacement th erapy on stroke prevention and stroke severity remains controversial. Previ ously we have shown that cerebral tissue infarction volume sustained after middle cerebral artery (MCA) occlusion is smaller in female than in male an imals. This protection is lost after ovariectomy but is restored by 17 beta -estradiol replacement. However, the therapeutic range for estradiol is su boptimal, since only doses resulting in a narrow range of plasma levels are protective in brain. The present study tested the hypothesis that a benzot hiophene analogue and selective estrogen receptor modulator, LY353381,HCl ( LY), reduces tissue infarction after MCA occlusion in estrogen-deficient, o variectomized female rats. Methods-Ovariectomized female Wistar rats received LY 10 mg/kg (n=16) or an equivalent volume of vehicle (n=14) by gavage for 5 to 8 days. Subsequentl y, each animal was anesthetized with halothane (1.2%) and treated with 2 ho urs of MCA occlusion by the intraluminal filament technique and 22 hours of recovery. Infarction volumes in the cerebral cortex and caudoputamen were determined by 2,3,5-triphenyltetrazolium chloride staining and digital imag e analysis. End-ischemic regional cerebral blood flow (CBF) was measured in separate animal cohorts by quantitative [C-14]iodoantipyrine autoradiograp hy. Results-Caudoputamen infarction was reduced by LY treatment (49+/-6% versus 64+/-4% of ipsilateral caudoputamen in LY and vehicle groups, respectively ; P<0.05). Cerebral cortical infarction was not different in the LY compare d with vehicle group (7+/-3% versus 13+/-4% of ipsilateral cerebral cortex, respectively). Intra-ischemic blood pressure, arterial blood gases, and te mporalis muscle temperature were controlled and equivalent between treatmen t groups. Averaged laser-Doppler flow during MCA occlusion was 36+/-3% of b aseline in the LY group versus 29+/-2% in the vehicle group. However, end-i schemic CBF or blood flow distribution within the MCA territory was not alt ered by LY treatment. Cortical or caudoputamen tissue volumes with end-isch emic CBF <20 mL/100 g per minute were similar in both groups. Conclusions-We conclude that LY confers neuroprotection from focal cerebral ischemia in caudoputamen in ovariectomized female rats. The mechanism of p rotection is not linked to preservation of ischemic cerebral blood flow, as determined by end-occlusion quantitative autoradiography.