Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions

Abstract

Recent studies describing the seemingly contradictory actions of estrogens in ischemic stroke injury have led us to reevaluate the circumstances under which estrogen therapy (ET) provides benefits against cerebral stroke and decipher its mechanisms of action. One prominent feature that follows stroke injury is massive central and peripheral inflammatory responses. Evidence now suggests that postischemic inflammatory responses strongly contribute to the extent of brain injury, and 17beta-estradiol (E(2)) may protect the ischemic brain by exerting antiinflammatory actions. In an attempt to explain recently reported dichotomous effects of E(2) in stroke injury, we tested the hypothesis that an extended period of hypoestrogenicity both prevents E(2) from protecting the brain against ischemia and simultaneously suppresses its antiinflammatory actions. We report that E(2) exerts profound neuroprotective action when administered immediately upon ovariectomy, but not when administered after 10 weeks of hypoestrogenicity. Consistently, E(2) treatment given immediately at the time of ovariectomy attenuated central and peripheral production of proinflammatory cytokines after ischemic stroke. In contrast, E(2) did not suppress production of proinflammatory molecules when it was administered after 10 weeks postovariectomy. These results demonstrate that a prolonged period of hypoestrogenicity disrupts both neuroprotective and antiinflammatory actions of E(2). Our findings may help to explain the results of the Women's Health initiative that reported no beneficial effect of ET against stroke because the majority of the subjects initiated ET after an extended period of hypoestrogenicity.

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…In fact, estradiol does not alter the inflammatory signaling cascade in microglia if it is administered after inflammatory stimuli ( [26,82,242]); in addition, a prolonged hormonal deprivation affects estrogen protective activity in ischemia and causes a null or even opposite response to exogenous hormone administration [224]. Collectively, the experimental Fig.…”

Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain

“…In rodents, the neuroprotective effect of E2 in the brain has been shown to be different depending on the timing of administration of E2 after ovariectomy. 47 In this regard, the data generated in the recent HRT trials 48 have to be reevaluated to include consideration of the age of subjects selected for HRT. The response of a 70-to 80-year-old woman who has not previously had HRT cannot be expected to be similar to that of a woman at menopause.…”

Interrelation between inflammation, thrombosis, and neuroprotection in cerebral ischemia

“…In fact, the presence of initial neural infl ammation is negatively correlated with serum estradiol levels (Wang et al , 2007 ). The proposed antiinfl ammatory action of estradiol is strengthened by fi ndings that 17 β -estradiol is neuroprotective when administered immediately upon ovariectomy but not when administered after 10 weeks of hypoestrogenicity, demonstrating that a prolonged period of hypoestrogenicity disrupts not only the neuroprotective but also the anti-infl ammatory actions of estradiol (Suzuki et al, 2007(Suzuki et al, , 2009 ). The fi rst cellular response in infl ammation is the activation and accumulation of neutrophils (Morganti -Kossmann et al, 2001 ).…”

“…Ischemic injury itself has been found to increase the expression of ER α in the cerebral cortex, without infl uencing ER β expression. Consequently, it is believed that it is this ER α re-expression after ischemic injury that mediates 17 β -estradiol ' s profound neuroprotection against ischemia (Dubal et al , 2001 ;Suzuki et al , 2007Suzuki et al , , 2009.…”