Estradiol exerts neuroprotective effects when administered after ischemic insult.

Abstract

17beta-Estradiol (E2) has been reported to exert neuroprotective effects when administered before an ischemic insult. This study was designed to determine whether E2 treatment after ischemia exerts the same effects and, if so, how long this therapeutic window remains open, and whether the effects are related to changes in cerebral blood flow (CBF). Female Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). In protocol 1, E2 was administered (100 microg/kg 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 received vehicle instead of E2. Two days after MCAO the animals were killed, and ischemic lesion volume was determined by 2,3,5-triphenyltetrazolium chloride staining. In protocol 2, CBF was monitored before and at 1, 24, and 48 hours in a group of animals receiving E2 or vehicle 0.5 hour after ischemia induction (INT, n=6; OVX, n=8; OVX+E2, n=6). Lesion volume was 20.9+/-2.2% and 21.8+/-1.2% in the INT and OVX groups, respectively. E2 was found to decrease lesion volume significantly when 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 administered at 0.5, 1, 2, 3, or 4 hours after MCAO, respectively. CBF decreased 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 OVX+E2 group 1 and 2 days after E2 administration. E2 exerts neuroprotective effects when administered after ischemia, 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.