Abstract 203: Chronic and Acute Estrogen Replacement Therapy Has Different Effects in Aged Animals After Experimental Stroke

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Introduction: The effect of estrogen replacement therapy (ERT) on stroke incidence and severity has been extensively debated. Clinical trials of ERT demonstrated an increased risk of stroke in treated women, but study participants were well past menopause when therapy was initiated. It has been suggested that detrimental effects of ERT may be unmasked after prolonged periods of hypoestrogenicity. To date, very few studies have examined the effect of ERT in aged animals although the timing of replacement may be critical to the neuroprotective effects of ERT. Hypothesis: We hypothesized that chronic estrogen replacement (CER) initiated in late middle age, would decrease infarct size after an induced stroke whereas acute estrogen replacement (AER) would have no beneficial effects in the aged female brain. Methods: CER was administered to aged C57BL6 mice from 17 to 20 months of age, and AER was initiated at 20 months of age. Both CER and AER treated mice were subjected to 90-minute middle cerebral artery occlusion (MCAO) at 20.5 months of age. Stroke outcomes at 24 hours of MCAO were measured. Protein levels of nuclear factor κB (NFκB), estrogen receptor α (ERα) and serum levels of pro-inflammatory cytokines were also examined. Results: Female mice that received CER showed improved stroke outcomes after MCAO (total infarct: CER vs. vehicle 34.7±2.4% vs. 58.2±2.6%; n=9/gp, p <0.05); whereas females that had AER did not. CER females exhibited diminished levels of NFκB translocation compared to AER females after stroke. AER females demonstrated both an increase in nuclear NFκB and enhanced expression of pro-inflammatory cytokines. The differential NFκB translocation was related to corresponding changes in ERα expression. Aged males benefited from ERT regardless of the timing of initiation of ERT, and had significantly reduced expression of pro-inflammatory markers after stroke compared to age-matched females. Conclusions: AER worsened stroke outcomes whereas CER was protective in aged females. A pro-inflammatory milieu emerges with age in females which was attenuated by CER treatment. Interestingly both AER and CER reduced stroke injury in aged males, suggesting sexually dimorphic effects on inflammation.