Differential modulation of estrogen receptors (ERs) in ischemic brain injury: a role for ERalpha in estradiol-mediated protection against delayed cell death.
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.
Dubal
Dena B
DB
Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.
Rau
Shane W
SW
Shughrue
Paul J
PJ
Zhu
Hong
H
Yu
Jin
J
Cashion
Adrienne B
AB
Suzuki
Shotaro
S
Gerhold
Lynnette M
LM
Bottner
Martina B
MB
Dubal
Sam B
SB
Merchanthaler
Istvan
I
Kindy
Mark S
MS
Wise
Phyllis M
PM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy*; D004958:Estradiol / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000502:physiology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D004958:Estradiol