Differential Modulation of Estrogen Receptors (ERs) in Ischemic Brain Injury: A Role for ERα in Estradiol-Mediated Protection against Delayed Cell Death

Abstract

Estradiol enhances plasticity and survival of the injured brain. Our previous work demonstrates that physiological levels of estradiol protect against cerebral ischemia in the young and aging brain through actions involving estrogen receptors (ERs) and alterations in gene expression. The major goal of this study was to establish mechanisms of neuroprotective actions induced by low levels of estradiol. We first examined effects of estradiol on the time-dependent evolution of ischemic brain injury. Because estradiol is known to influence apoptosis, we hypothesized that it acts to decrease the delayed phase of cell death observed after middle cerebral artery occlusion (MCAO). Furthermore, because ERs are pivotal to neuroprotection, we examined the temporal expression profiles of both ER subtypes, ERalpha and ERbeta, after MCAO and delineated potential roles for each receptor in estradiol-mediated neuroprotection. We quantified cell death in brains at various times after MCAO and analyzed ER expression by RT-PCR, in situ hybridization, and immunohistochemistry. We found that during the first 24 h, the mechanisms of estradiol-induced neuroprotection after MCAO are limited to attenuation of delayed cell death and do not influence immediate cell death. Furthermore, we discovered that ERs exhibit distinctly divergent profiles of expression over the evolution of injury, with ERalpha induction occurring early and ERbeta modulation occurring later. Finally, we provide evidence for a new and functional role for ERalpha in estradiol-mediated protection of the injured brain. These findings indicate that physiological levels of estradiol protect against delayed cell death after stroke-like injury through mechanisms requiring ERalpha.

Neuronal Estrogen Receptor-α Mediates Neuroprotection by 17β-Estradiol

“…Quantification of ERa mRNA by real-time reverse transcription PCR 24 h after MCAO confirmed this finding. Estrogen receptor-a mRNA was upregulated in the ischemic ipsilateral cortex compared with the contralateral side ( Figure 4B) in accordance with a report that cerebral ischemia induces ERa expression (Dubal et al, 2006). However, in CaMKIICre/ER fl/fl mice, ERa expression was markedly reduced both in the ischemic and the contralateral sides ( Figure 4B).…”

Age-dependent Effects of 17β-estradiol on the Dynamics of Estrogen Receptor β (ERβ) Protein–Protein Interactions in the Ventral Hippocampus

“…ER␤ has been characterized as predominantly antiproliferative and pro-apoptotic in cancer models, in contrast to the proliferative and antiapoptotic role of ER␣. However, in the brain, both receptors demonstrate protection against various neurological insults such as ischemia and glutamate toxicity (26,27). E2 can induce anti-apoptotic factors such as Bcl-2 (28 -31), and overexpression of Bcl-2 can induce nuclear localization of factors such as ANXA1 (32).…”

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

“…Although the neuroprotective properties of beta-estradiol [51] have been already reported in different diseases and models [52,53], and estrogen effects on neuronal viability have been demonstrated both in vitro and in in vivo [54,55], the underlying molecular mechanisms are still elusive. Our data indicate that beta-estradiol treatment is neuroprotective since it results in increased cell survival and proliferation, accompanied by reduction of ubiquitinated protein inclusions.…”