Periodic Estrogen Receptor-Beta Activation: A Novel Approach to Prevent Ischemic Brain Damage

In women, the risk for cerebral ischemia climbs rapidly after menopause. At menopause, production of ovarian hormones; i.e., progesterone and estrogen, slowly diminishes. Estrogen has been suggested to confer natural protection to premenopausal women from ischemic stroke and some of its debilitating consequences. This notion is also strongly supported by laboratory studies showing that a continuous chronic 17 beta-estradiol (E-2; a potent estrogen) regimen protects brain from ischemic injury. However, concerns regarding the safety of the continuous intake of E-2 were raised by the failed translation to the clinic. Recent studies demonstrated that repetitive periodic E-2 pretreatments, in contrast to continuous E-2 treatment, provided neuroprotection against cerebral ischemia in ovariectomized rats. Periodic E-2 pretreatment protects hippocampal neurons through activation of estrogen receptor subtype beta (ER-beta). Apart from neuroprotection, periodic activation of ER-beta in ovariectomized rats significantly improves hippocampus-dependent learning and memory. Difficulties in learning and memory loss are the major consequence of ischemic brain damage. Periodic ER-beta agonist pretreatment may provide pharmacological access to a protective state against ischemic stroke and its debilitating consequences. The use of ER-beta-selective agonists constitutes a safer target for future research than ER-alpha agonist or E-2, inasmuch as it lacks the ability to stimulate the proliferation of breast or endometrial tissue. In this review, we highlight ER-beta signaling as a guide for future translational research to reduce cognitive decline and cerebral ischemia incidents/impact in post-menopausal women, while avoiding the side effects produced by chronic E-2 treatment.