Acute and chronic estradiol treatments reduce memory deficits induced by transient global ischemia in female rats

Abstract

Transient global ischemia induces selective, delayed neuronal death in the hippocampal CA1 and delayed cognitive deficits. Estrogen treatment ameliorates hippocampal injury associated with global ischemia. Although much is known about the impact of estrogen on neuronal survival, relatively little is known about its impact on functional outcome assessed behaviorally. We investigated whether long-term estradiol (21-day pellets implanted 14 days prior to ischemia) or acute estradiol (50 microg infused into the lateral ventricles immediately after ischemia) attenuates ischemia-induced cell loss and improves visual and spatial working memory in ovariectomized female rats. Global ischemia significantly impaired visual and spatial memory, assessed by object recognition and object placement tests at 6-9 days. Global ischemia did not affect locomotion, exploration, or anxiety-related behaviors, assessed by an open-field test at 6 days. Long-term estradiol prevented the ischemia-induced deficit in visual working memory, maintaining normal performance in tests with retention intervals of up to 1 h. Long-term estradiol also prevented ischemia-induced deficits in spatial memory tests with short (1 and 7 min), but not longer (15 min), retention intervals. Acute estradiol significantly improved visual memory assessed with short retention intervals, but did not prevent deficits in spatial memory. Acute estradiol significantly increased the number of surviving CA1 neurons, assessed either at 7 days after ischemia or after the completion of behavioral testing 9 days after ischemia. In contrast, chronic estradiol did not reduce CA1 cell death 9 days after ischemia. Thus, long-term estradiol at near physiological levels and acute estradiol administered after ischemic insult improve functional recovery after global ischemia. These findings have important implications for intervention in the neurological sequellae associated with global ischemia.

Rapid enhancement of two-step wiring plasticity by estrogen and NMDA receptor activity

“…After ischemia, an increase in spine turnover is observed (29), as is an increase in E2 synthesis (30), which is suggestive of a putative natural recovery mechanism. Animal models of stroke have demonstrated that E2 treatment after ischemic insult significantly improves cortical memory normally disrupted by ischemia (31). It is intriguing to speculate that E2-induced wiring plasticity may in part underlie this recovery and that this mechanism of increased connectivity may be exploited to aid in the recovery from cortical dysfunction induced by brain injury.…”

Effects of multiparity on recognition memory, monoaminergic neurotransmitters, and brain-derived neurotrophic factor (BDNF)

“…This hypothesis is also consistent with a role for both CA1 and septum in memory performance. Lesions to the CA1 significantly impair performance on OR and OP tasks (Broadbent et al, 2004;Gulinello et al, 2006); OP in particular is dependent on an intact hippocampus and/or fornix (Ennaceur and Aggleton, 1994;Ennaceur et al, 1997;Mumby et al, 2002;Broadbent et al, 2004). Similarly, lesions to the dorsal hippocampus (containing CA1 and septal regions) impair performance on the Morris water maze to the same extent as lesions of whole hippocampus (Clark et al, 2005).…”

Gender and the injured brain

“…12-14 Although most of these animal studies emphasized infarct size and cell loss early after the insult, chronic estrogen supplementation also improved functional outcome. 15, 16 The effects of chronic estrogen exposure in these models may explain some of the female advantage in IBI, and they are the focus of recent studies in primary stroke prevention. However, since long-term treatment before a perioperative brain insult is obviously not an option for neuroprotection, the efficacy of acute treatment with estrogen in the perioperative setting at or after onset of ischemia has also been tested in experimental ischemia and found to reduce brain damage.…”

“…33 This may contribute to the improved memory function outcome after ischemia that is seen in estrogensupplemented animals. 16 In classical estrogen signaling, 17β-estradiol (E2), the predominant human estrogen, binds to an estrogen receptor (ER), usually ER-α or ER-β, which translocates to the nucleus and binds to an estrogen-response element (ERE) on the target gene to activate transcription. Both ER-α and ER-β are widely expressed under physiologic conditions in all cell types throughout the brain, i.e., neurons, glia, and endothelial cells, including in ischemia-sensitive areas such as neocortex and hippocampus.…”