Estrogen and ischemic neuroprotection: an integrated view

https://doi.org/10.1016/S1043-2760(03)00076-6Get rights and content

Abstract

Women are protected from stroke in their early years relative to men. This native neuroprotection is lost within ten years of the menopause, an observation commonly attributed to loss of estrogen with age. Data are now available from large, randomized, clinical trials that question the use of hormone replacement therapy (HRT) for either the primary or secondary prevention of vascular disease and stroke. In contrast to these studies of disease prevention, evidence from the bench suggests that estrogen is a potent neuroprotectant, demonstrating cell salvage from ischemic death pathways. This apparent dichotomy between the limitation of HRT in ameliorating complex disease development vs the excellent performance of estradiol in containing experimental brain damage remains to be understood.

Section snippets

Neuroprotective effects of estradiol in vivo

It has been known for almost three decades that female animals have a lower incidence of naturally occurring stroke than do males. When strains of spontaneously hypertensive animals were followed into old age, female rats had significantly lower rates of spontaneous stroke and death. Surgical loss of estrogen by ovariectomy abolished this benefit, with restoration by estrogen replacement [3]. When cerebral ischemia is induced (by occlusion of a supplying cerebral vessel), females sustain less

Estradiol signaling in neuroprotection

Early autoradiographic studies demonstrated numerous sites of nuclear radioactivity accumulation after [3H]-estradiol injection into brain and spinal cord of both sexes, suggesting the presence of estrogen receptors (ERs) well outside brain areas classically linked to reproductive function. At present, there are two known estrogen receptor subtypes, α and β 18, 19, which share homology in DNA-binding domains and potentially activate the same transcriptional elements. ERα and ERβ distributions

Pan-cellular mechanisms

The neuroprotective mechanisms of estrogen that are relevant to cerebral ischemia and stroke can be viewed as either pan-cellular or cell-type specific. The antioxidant activity of estrogen is one of the clearest examples of its pan-cellular mechanisms. Increased oxidative stress is thought to underlie some of the damaging effects of brain injury. Many estrogens have well established and potent lipid antioxidant activity, particularly the catechol estrogens (2-hydroxyestrone and

Vascular targets

Given the wide range of vascular tissues that are estrogen sensitive in both females and males, acute and chronic atheroprotective mechanisms are important [31]. Furthermore, ERs have been identified in vascular endothelium, smooth muscle and platelets, so that brain blood vessels must be considered as estrogen targets for cytoprotection. For example, chronic estrogen deprivation increases leukocyte adhesion and infiltration through vascular endothelium in rat cerebral vessels, exacerbating

Estrogen and angiogenesis

Angiogenesis, a process mediated by migration and proliferation of endothelial and smooth muscle cells, leading to new vessel formation (reviewed in [43]), plays a pivotal role in the long-term outcome from ischemic damage [44]. Estradiol induces endothelial proliferation and migration through interaction with the ER, as demonstrated by evidence of impaired angiogenesis after treatment with ER antagonists [45]. The angiogenic effects of estrogen might be mediated in part by vascular endothelial

Neuronal targets

Emerging evidence suggests that estradiol directly protect neurons when tested in culture (reviewed in [27]) or in animal models where blood flow effects have been controlled or excluded [41] (reviewed in [8]).

Glial targets

There is increased recognition of an interaction between estrogen and glia, the predominant cell type in brain (reviewed in [65]). Induction of ERα in astrocytes after application of excitotoxins in vivo, peaking at one week after injury, has been described [66]. Reactive astrocytes in the injury zone display increased activity of P450 aromatase, suggesting that androgens could be metabolized to estrogens with consequent neuroprotection [67]. In turn, estrogen induces astrocytic growth factor

Conclusions

Further work is needed to understand how sex and reproductive steroids impact on stroke sensitivity and the fundamental pathological mechanisms underlying cerebrovascular disease. A more integrated analysis of all cell types involved in cerebral ischemia, including vascular endothelium and glia, is required if the neuroprotective potential of estradiol is to be harnessed and translated to humans. Potential crosstalk of molecular mechanisms among the many target cell types of estrogen probably

Acknowledgements

This work was supported by the American Stroke Association (LDM), Hazel K. Goddess Fund for Stroke Research in Women (LDM) and NIH grants NS33668, NS20020 and NR03521.

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