Estrogen exacerbates cerebral vascular leukocyte activity in diabetic rats via a RAGE‐related mechanism

In striking contrast to its effects in non‐diabetics, estrogen (E 2 ) replacement therapy (ERT) in diabetic ovariectomized (OVX) females potentiates post‐ischemic leukocyte adhesion and brain damage. In this study, we tested the hypothesis that this transformation of E 2 from a counter‐ to a pro‐inflammatory substance was due to an enhanced contribution from the receptor for advanced glycation end‐products (RAGE). To monitor cerebral vascular inflammatory activity, rhodamine 6G‐labeled leukocytes were observed through a closed cranial window. Pial venular leukocyte adherence and infiltration was monitored over 10 h reperfusion after 20–30 min transient forebrain ischemia (TFI) in intact, OVX, and E 2 ‐treated OVX (OVX+E 2 ) diabetic (streptozotocin) females. The role of RAGE was tested via brain surface applications of: 1) RAGE antisense (AS) oligodeoxynucleotide (ODN); or 2) a soluble RAGE ectodomain decoy inhibitor (sRAGE). As previously reported by us, post‐ischemic leukocyte adhesion was highest in the OVX+E 2 group. Leukocyte infiltration, if it occurred, was observed at >6 hours post‐ischemia, but essentially only in diabetic OVX+E 2 and, to a lesser extent, intact females. Pretreatment with RAGE AS‐ODN or sRAGE attenuated post‐ischemic leukocyte adhesion in the diabetic OVX+E 2 (~90%) and intact (~50%) groups, but had no effect on untreated OVX females. These findings suggest that the presence of estrogen (i.e., intact and OVX+E 2 rats) may promote RAGE‐associated cerebral inflammatory activity, and implies that targeting RAGE may restore the neuroprotective effect of ERT in diabetic females. Supported by DK65629, HL52594.