Estrogen replacement treatment in diabetic ovariectomized female rats potentiates postischemic leukocyte adhesion in cerebral venules

Background and Purpose-Chronic 17 beta-estradiol (E-2) replacement therapy in ovariectomized (OVX) female rats reduces leukocyte adhesion and brain damage after transient forebrain ischemia. Recently, we found that E-2 treatment in diabetic OVX females was associated with enhanced postischemic neuropathology. We tested the hypothesis that in chronically hyperglycemic diabetic OVX females, chronic E-2 replacement potentiates post-transient forebrain ischemia leukocyte adhesion. Methods-Pial venules were observed through closed cranial windows. Adherence of rhodamine 6G-tagged leukocytes was monitored before and 10 hours after transient forebrain ischemia (20 minutes right common carotid artery occlusion plus hemorrhagic hypotension) in intact, untreated OVX and E-2-treated OVX females rendered diabetic via streptozotocin. Leukocyte adhesion was quantitated as the percentage venular area occupied by adherent leukocytes. Results-At 2 hours after transient forebrain ischemia, a similar low level of leukocyte adhesion was seen in the 3 groups (<3% of the venular area). Starting at approximate to 4 hours after ischemia, leukocyte adhesion in the E-2-treated OVX females rose to significantly higher levels compared with the other groups. Relative to the 2-hour value, the level of adhesion at 10 hours was 12.5-fold, 4-fold, and 5-fold greater in the E-2-treated OVX, OVX, and intact groups, respectively. Leukocyte extravasation ( beginning after 6 hours of reperfusion) was observed in a majority (64%) of the E-2-treated animals, with limited or no extravasation seen in the intact or OVX groups. Conclusions-These results suggest that factors associated with diabetes and chronic hyperglycemia convert E-2 from a counterinflammatory to a proinflammatory substance in an ischemic setting.