Estradiol as an Acute Neuroprotectant

Endogenous estrogens strongly influence outcome to an ongoing ischemic event in the female. In rodents, ischemic outcome varies with the stage of the estrous cycle, with lesser infarct volumes in proestrus (period of high estradiol) as compared to metestrus (period of low estradiol) (17). Male-female differences in stroke sensitivity can be blunted by ovariectomy or by natural declination of estrogen levels with aging (18,19). Exogenous estradiol treatment before or after focal cerebral ischemia at physiologic levels reduces ischemic tissue death. Almost universally, the steroid reduces brain injury after an ischemic, glutamatergic, pro-oxidant, or proapoptotic insult (20,21). Accordingly, it is potentially important as an acute neuroprotectant.

However, several points should be critically evaluated in the plethora of animal and cell injury studies. In both permanent and transient focal cerebral ischemia models, estrogen is effective in estrogen-deficient rodents (males, ovariectomized females, and reproductively senescent females). However, the therapeutic range of "neuroprotective" steroid doses is not large; best results are obtained in most studies with low, physiologic levels of the steroid. No studies of long-term estrogen exposure have been conducted; therefore, the effect of treatment duration is unclear. Almost all of our understanding of estrogen's neuroprotection arises from rodent data. Few data are available in higher-order, gyroencephalic animals, such as cat or nonhuman primates. Most studies have evaluated 17P-estradiol, not the potent estrogen conjugates that are utilized in HRT. Few laboratories have demonstrated deleterious effects of estrogen, although a large variety of animal and cell models have been evaluated. In two studies of severe cerebral ischemia induced by permanent focal cerebral ischemia (22) or global cerebral ischemia from four-vessel occlusion (23), estradiol enhanced tissue damage. Accordingly, we have few data that define and distinguish the neuroprotectant estrogen from the proinjury estrogen.

Lastly, it must be emphasized that estrogen's actions in the brain and in the cerebral vasculature are quite complex. Most estrogens are vasoactive and have potent effects on endothelium and vascular smooth muscle cells of brain blood vessels. For example, 17P-estradiol can increase cerebral blood flow during and after vascular occlusion, but high doses are prothrombotic. The steroid likely utilizes multiple cellular signaling mechanisms; likely mechanisms include gene transcription of neuroprotective genes, as well as rapid receptor-mediated and receptor-independent effects. These latter actions involve phosphorylation cascades and intracellular signaling that activate ion channels, neurotransmitter receptors, and enzymes, such as endothelial nitric oxide synthase. Many estrogens have potent, concentration-dependent lipid antioxidant activity, although typically at supraphysiologic concentrations. In total, estrogen's very breadth of actions as a multifunctional molecule makes it an ideal prototype for developing future neuroprotectants.

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