Estrogen preconditioning: A promising strategy to reduce inflammation in the ischemic brain

During the premenopausal phase of a woman's life, estrogen naturally protects against ischemic brain damage and its debilitating consequence of cognitive decline. However, the decline in estrogen at menopause exponentially increases a women's risk for cerebral ischemia and its severity. Supplementation of estrogen during menopause is the most logical solution to abate this increased risk for cerebral ischemia; however, continuous therapy has proven to be contraindicative. Studies from our laboratory over the past decade have shown that a single bolus or long-term periodic 17β-estradiol treatment(s) two days prior to ischemia mimics ischemic preconditioning-conferred protection of the brain in ovariectomized or reproductively senescent female rats. These studies also demonstrated that 17β-estradiol-induced preconditioning (EPC) requires estrogen receptor (ER)-subtype beta (ER-β) activation. ER-β is expressed throughout the brain, including in the hippocampus, which plays a key role in learning and memory. Because periodic activation of ER-β mitigates post-ischemic cognitive decline in ovariectomized female rats, it can be surmised that EPC has the potential to reduce post-ischemic damage and cognitive decline in females. Estrogens are key anti-inflammatory agents; therefore this review discusses the effects of EPC on the inflammasome. Furthermore, as we now clearly know, the brain acts differently in males and females. Indeed, neurodegenerative diseases, including cerebral ischemia, and pharmacological drugs affect males and females in different ways. Thus, inasmuch as the National Institutes of Health and the Stroke Treatment Academic Industry Roundtable (STAIR) consortium mandate inclusion of female experimental animals, this review also discusses the need to close the gap in our knowledge in future studies of EPC in female animal models of cerebral ischemia.