Review
Neuroprotective actions of estradiol and novel estrogen analogs in ischemia: Translational implications

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Abstract

This review highlights our investigations into the neuroprotective efficacy of estradiol and other estrogenic agents in a clinically relevant animal model of transient global ischemia, which causes selective, delayed death of hippocampal CA1 neurons and associated cognitive deficits. We find that estradiol rescues a significant number of CA1 pyramidal neurons that would otherwise die in response to global ischemia, and this is true when hormone is provided as a long-term pretreatment at physiological doses or as an acute treatment at the time of reperfusion. In addition to enhancing neuronal survival, both forms of estradiol treatment induce measurable cognitive benefit in young animals. Moreover, estradiol and estrogen analogs that do not bind classical nuclear estrogen receptors retain their neuroprotective efficacy in middle-aged females deprived of ovarian hormones for a prolonged duration (8 weeks). Thus, non-feminizing estrogens may represent a new therapeutic approach for treating the neuronal damage associated with global ischemia.

Research highlights

Estradiol pretreatment attenuates ischemia-induced death of hippocampal neurons. ► Estradiol given immediately after ischemia is highly neuroprotective. ► Estradiol treatment improves cognitive outcomes after global ischemia. ► Estrogens retain their neuroprotective efficacy in hormone-withdrawn older females. ► The transcription factor CREB may be a downstream mediator of estradiol protection.

Introduction

Stroke is the third leading cause of death in the United States and the primary cause of disabilities in adults [111], [126], [214]. Of the 600,000 new victims each year, 30% die and another nearly 30% become severely and permanently disabled. Transient global ischemia arises as a consequence of cardiac arrest, cardiac surgery, profuse bleeding, near-drowning and carbon monoxide poisoning and affects ∼200,000 Americans each year [111], [126], [214]. Transient global ischemia causes selective, delayed death of hippocampal CA1 neurons in humans and can produce serious neurologic sequellae, of which cognitive deficits are most prominent. There are still remarkably few safe and effective treatments to reduce the neuronal cell death and cognitive dysfunction associated with ischemia. It is now well established that endogenous and exogenous estrogens exert profound neuroprotective effects in animal models of focal (stroke) and global ischemia [20], [106], [4], [81], [121], [168], [179], [169], [66], [149], [70]. Dietary intake of phytoestrogens (plant-derived estrogens) can also improve outcomes after focal [22], [114] and global ischemia in rats [108]. In cultured neurons, estrogens can reduce cell death induced by excitotoxins (e.g., glutamate), oxidative stress, β-amyloid, and serum deprivation [12], [21], [117], [170], [5], [133], [58], [124]. Moreover, estrogens are reported to reduce ischemia-induced damage to tissues such as kidney and heart and to reduce apoptosis in vascular smooth muscle [173], [17], [41], [83], [202]. A multicenter study of postmenopausal women also reported that longer lifetime exposure to ovarian estrogens may protect against ischemic stroke [37]. Thus, estrogens hold great promise as potential therapeutic agents in treatment of ischemia. Yet, the clinical use of estradiol and related estrogens in menopausal women remains controversial. Large clinical trials such as the Women’s Health Initiative (WHI) and the Heart and Estrogen/Progestin Replacement Study (HERS) called into question the ability of hormone treatment to reduce the occurrence or incidence of cardiovascular disease, stroke and dementia in postmenopausal women [48], [73], [147], [152], [153]. Another clinical trial, the Women Estrogen Stroke Trial (WEST), reported no beneficial effects of estradiol on stroke incidence; indeed postmenopausal women with estradiol treatment had an increased risk of stroke and worse neurological outcomes [189]. The current situation underscores the importance of animal studies to address unanswered questions regarding the efficacy of hormone treatment to reduce the extent of ischemia-induced neuronal damage and associated cognitive impairment.

Our laboratories initiated studies on the neuroprotective actions of the most abundant ovarian estrogen, 17β-estradiol (hereafter referred to as estradiol), in animal models of global ischemia about 10 years ago. Global ischemia induced by four-vessel occlusion (4-VO; see Fig. 1A) in rats is possibly the best established animal model of global ischemia [141]. A brief episode (10 min) induces selective death of CA1 pyramidal neurons and, as in humans, results in delayed onset of cognitive neurological deficits [134]. Inhibitory interneurons of the CA1 and virtually all neurons in the nearby CA2 or transition zone, CA3 and dentate gyrus survive. With the exception of a few scattered hilar neurons and/or pyramidal neurons in cortex, other neurons do not exhibit cell death. Although the 4-VO model virtually ablates hippocampal CA1 pyramidal neurons by 7 days, the onset of histologically detectable neuronal death is delayed by 2–3 days [142], enabling molecular studies of cells “destined to die” under conditions in which cell loss is not yet evident. This model is also clinically relevant to global ischemia associated with cardiac arrest in humans and offers the ability to compare changes in gene expression in neurons of the vulnerable CA1 with those of the resistant CA3. Moreover, because blood circulation to the cranium is completely blocked (rather than reduced by hypotension), monitoring of blood flow is not necessary. It has not been possible to exploit the power of transgenic mice to study global ischemia, because it is difficult to achieve delayed, selective hippocampal cell death in most mouse strains.

At the time we began our work, there was limited evidence that estradiol reduced CA1 neuronal death and ameliorated the cognitive deficits associated with ischemic cell death after global ischemia [30], [102], [175], [192]. As described in the following review, we have now explored a number of clinically relevant issues, including the timing and route of hormone administration, the cellular and molecular mechanisms of estradiol’s neuroprotective actions, the degree to which neuronal preservation correlates with functional outcomes, and the effects of age and prolonged hormone withdrawal.

Section snippets

Pretreatment with estradiol in young animals

We first examined the impact of estradiol administration on global ischemia-induced neuronal death in young adult male gerbils. The two vessel occlusion model in gerbils affords a clinically relevant surgical model of global ischemia which is relatively simple and requires a shorter duration of occlusion (5 min) relative to rats. To mimic the effect of long-term estradiol therapy in humans, we delivered estradiol to gerbils via subcutaneous, timed-release pellets for 2 weeks prior to induction of

Pretreatment with estradiol in older animals

Our findings and results from several independent laboratories cited above clearly show that estrogens protect against global ischemia-induced hippocampal injury and improve functional outcomes when administered to young animals. Rates of heart disease increase substantially in postmenopausal women, placing them at increased risk for a global ischemic event. The risk of cardiovascular disease is also increased in younger women who experience ovarian hormone disruption as a consequence of

Acute treatment with estradiol after reperfusion

As described above, our experiments lead us to conclude that estradiol pretreatment (i.e., initiated 2 weeks prior to insult) significantly attenuates ischemia-induced neuronal death in hippocampal CA1, and that the benefits of this treatment (at least with respect to neuronal survival) are retained in older individuals even after prolonged ovarian hormone deprivation. Nonetheless, such pretreatment regimens have limited translational potential for three major reasons. First, the results of

Conclusions and unresolved questions

This review described the strategies we adopted over the past decade to investigate the neuroprotective efficacy of estradiol and other estrogenic agents in animal models of transient global ischemia, summarized our key findings and discussed these in relationship to published work from other investigators. In agreement with a vast literature in rodents and in cultured neurons, we find that estradiol rescues a significant number of CA1 pyramidal neurons that would otherwise die in response to

Acknowledgments

Supported by R01 MH41414, R01 NS045693, R01 AG AG027702, American Heart Association Development Award 0335285N, ISCIII RETICS-RENEVAS RD06/0026/0006 and the F.M. Kirby Program in Neural Repair and Protection. The authors wish to acknowledge Dr. Diane Lebesgue for providing comments on the manuscript.

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