Estradiol exerts neuroprotective effects when administered after ischemic insult

Background and Purpose-17 beta-Estradiol (E2) has been reported:tb exert :n europrotective effects when administered before an ischemic insult. This st udy was designed to determine whether E2 treatment after ischemia exerts th e same effects and, if so, how long this therapeutic window remains open, a nd whether the effects are related to changes in cerebral blood flow (CBF). Methods-Female Sprague-Dawley rats were subjected to permanent middle cereb ral artery occlusion (MCAO). In protocol 1, E2 was administered (100 mu g/k g IV followed immediately by subcutaneous implantation of crystalline E2 in a silicone elastomer tube) to ovariectomized females (OVX+E2) at 0.5 (n=8) , 1 (n=6), 2 (n=7), 3 (n=6), or 4 (n=9) hours after: MCAO, Intact (INT; n=6 ) and ovariectomized females (OVX; n=12) were subjected to MCAO and receive d vehicle instead of E2. Two days after MCAO the animals were killed, and i schemic lesion volume was determined by 2,3,5-triphenyltetrazolium chloride staining. In protocol 2,CBF was monitored before and at 1, 24, and 48 hour s in a group of animals receiving E2 or vehicle 0.5 hour after ischemia ind uction (INT, n=6; OVX, n=8 OVX+E2, n=6). Results-Lesion volume was 20.9+/-2.2% and 21.8+/-1.2% in the INT and OVX gr oups, respectively. E2 was found to decrease lesion volume significantly wh en administered within 3 hours after MCAO. The lesion volumes were 6.3+/-0. 5%, 10.3+/-2.1%, 11.8+/-1.8%, 13.5+/-1.6%, and 17.9+/-2.8% when E2 was admi nistered at 0.5, 1, 2, 3, or 4 hours after MCAO,: respectively. CBF decreas ed to 43.1+/-2.2% and 25.4+/-1.0% in the INT and OVX animals, respectively, at 5 minutes after MCAO. In comparison to OVX rats, CBF was not different at 1 hour after E2 administration but was increased significantly in the OV X+E2 group 1 and 2 days:after E2: administration. Conclusions-E2 exerts neuroprotective effects when administered;after ische mia, with a therapeutic window in a permanent focal cerebral ischemia model of approximately 3 hours; This effect of estradiol was associated with no immediate change in blood flow but with a delayed increase in CBF.