Effects of estrogen in an aged animal model of stroke

Abstract

In 2000, approximately 10 million women were taking hormone replacement therapy (HRT) for alleviation of menopausal symptoms. A number of prior animal studies also suggested that HRT may be neuroprotective and cardioprotective as well. Although estrogen is neuroprotective in young adult animal models of stroke, clinical trials demonstrate that estrogen increases the incidence and severity of stroke in aged women. We have previously shown that experimental stroke pathophysiology differs between young adult and aged rats. In the first study, we show that aged rats treated with 17!-estradiol had significantly increased infarct volumes compared to placebo-treated aged rats. Young adult rats treated with 17!-estradiol had significantly decreased infarct volumes and functional outcome compared to ovariectomized young adult rats. Aged female rats treated with 17!-estradiol had decreased post-ischemic GFAP-positive astrocytes and altered astrocyte morphology. In the second study, we investigate a potential mechanism involved in the deleterious effects of estrogen in the aged female rat brain. In rats chronically supplemented with estrogen or placebo, we measure a significant reduction in erythropoietin (EPO) receptor mRNA in the ischemic cortex following transient occlusion of the middle cerebral artery. We also observe decreased EPO-receptor protein expression in the penumbral cortex and striatum using immunohistochemical techniques. In a second group of rats, we confirm that EPO administration attenuates estrogen-induced increase in infarct volume, and is accompanied by decreased expression of ER" in the ischemic penumbra. In the third study, we assess hippocampal-dependent memory using the 8-arm radial maze in young adult and aged female rats following middle cerebral artery occlusion with fibrin clot and tissue plasminogen activator reperfusion. Aged rats required greater number of sessions to become trained and had increased trial duration, suggesting reduced locomotor activity. Although baseline differences in reference and working memory errors were observed, they did not reach significance. Following MCAO, no significant differences were found in reference or working memory errors between young adult and aged rats. Finally, we investigate the effects of estrogen supplementation on structure and function of lacrimal and Meibomian glands in aged female rats. Following 90 days of estrogen supplementation in aged female rats, a reduction in tear volume and tear break up time in estrogen treated rats was accompanied by increased connective tissue fibrosis in both extraorbital and intraorbital lacrimal glands and reduced acinar lumen in the intraorbital lacrimal glands. These functional and structural changes are likely mediated by ER", as estrogen treatment led to upregulation of ER" expression in lacrimal and Meibomian glands. Chapter One Literature Review