Postischemic estrogen reduces hypoperfusion and secondary ischemia after experimental stroke

Background and Purpose - Estrogen is a known neuroprotective and vasoprotective agent in experimental cerebral ischemia. Preischemic steroid treatment protects animals of both sexes from focal cerebral ischemia. This study determined whether intravenous estrogen acts as a vasodilator when administered on reperfusion and whether the resulting increase in cerebral blood flow (CBF) provides tissue protection from middle cerebral artery occlusion. Methods - Adult male Wistar rats were treated with reversible middle cerebral artery occlusion (2 hours), then infused with intravenous estrogen (Premarin; 1 mg/kg) or vehicle during the first minutes of reperfusion (n= 15 per group). Cortical laser-Doppler flowmetry was used to assess adequacy of occlusion. Ischemic lesion volume was determined at 22 hours after occlusion by 2,3,5-triphenyltetrazolium chloride staining and image analysis. Cortical and striatal CBF was measured by ¹⁴[C]iodoantipyrine autoradiography at 10 (n= 10) or 90 (n= 11) minutes of reperfusion. Results - As expected, supraphysiological plasma estrogen levels were achieved during reperfusion (estrogen, 198±45 pg/mL; vehicle, 6±5; P=0.001). Physiological variables were controlled and not different between groups. Total hemispheric infarction was reduced in estrogen-treated rats (estrogen, 49±4% of ipsilateral structure; vehicle, 33±5%; P=0.02), which was most pronounced in striatum (estrogen, 40±6% of ipsilateral striatum; vehicle, 60±3%; P=0.01). CBF recovery was strikingly increased by estrogen infusion at 10 minutes in frontal (estrogen, 102±12 mL/100 g per minute; vehicle, 45±15; P=0.01) and parietal cortex (estrogen, 74±15 mL/100 g per minute; vehicle, 22±13: P=0.028) and throughout striatum (estrogen, 87±13 mL/100 g per minute; vehicle, 25±20; P=0.02). Hemispheric volume with low CBF recovery (eg, <20 mL/100 g per minute) was smaller in estrogen-treated animals (estrogen, 73±18 mm³; vehicle, 257±46; P=0.002). However, differences in CBF recovery could not be appreciated between groups by 90 minutes of reperfusion. Conclusions - Acute estrogen therapy during reperfusion improves tissue outcome from experimental stroke. The steroid rapidly promotes CBF recovery and reduces hemispheric no-reflow zones. This beneficial effect appears only during early reperfusion and likely complements other known mechanisms by which estrogen salvages brain from focal necrosis.