Acute Administration of Non-Classical Estrogen Receptor Agonists Attenuates Ischemia-Induced Hippocampal Neuron Loss in Middle-Aged Female Rats

Lebesgue, Diane; Traub, Michael; Butte-Smith, M. De; Chen, Christopher; Zukin, R. Suzanne; Kelly, Martin J.; Etgen, Anne M.

doi:10.1371/journal.pone.0008642

Cited by 136 publications

(124 citation statements)

References 54 publications

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“…Along these lines, our study found that low-dose E2 replacement in middle-aged rats was capable of exerting significant neuroprotection against GCI, in contrast to a lack of protection in old rats. Our finding that E2 is still protective in middle-aged rats is consistent with previous reports by others in both focal and GCI models (33)(34)(35). Low-dose E2 therapy would be preferred in humans so as to minimize negative side effects.…”

Section: Discussionsupporting

confidence: 92%

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

Zhang

Han

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

127

132

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Recent work suggests that timing of 17β-estradiol (E2) therapy may be critical for observing a beneficial neural effect. Along these lines, E2 neuroprotection, but not its uterotropic effect, was shown to be lost following long-term E2 deprivation (LTED), and this effect was associated with a significant decrease of estrogen receptor-α (ERα) in the hippocampus but not the uterus. The purpose of the current study was to determine the mechanism underlying the ERα decrease and to determine whether aging leads to a similar loss of hippocampal ERα and E2 sensitivity. The results of the study show that ERα in the rat hippocampal CA1 region but not the uterus undergoes enhanced interaction with the E3 ubiquitin ligase C terminus of heat shock cognate protein 70 (Hsc70)-interacting protein (CHIP) that leads to its ubiquitination/proteasomal degradation following LTED (10-wk ovariectomy). E2 treatment initiated before but not after LTED prevented the enhanced ERα-CHIP interaction and ERα ubiquitination/degradation and was fully neuroprotective against global cerebral ischemia. Administration of a proteasomal inhibitor or CHIP antisense oligonucleotides to knock down CHIP reversed the LTED-induced down-regulation of ERα. Further work showed that these observations extended to natural aging, because aged rats showed enhanced CHIP interaction; ubiquitination and degradation of both hippocampal ERα and ERβ; and, importantly, a correlated loss of E2 neuroprotection against global cerebral ischemia. In contrast, E2 administration to middle-aged rats was still capable of exerting neuroprotection. As a whole, the study provides support for a "critical period" for E2 neuroprotection of the hippocampus and provides important insight into the mechanism underlying the critical period.estradiol | neuroendocrine | steroid | stroke B asic science and clinical observation studies have provided evidence of a beneficial effect of 17β-estradiol (E2) on cardiovascular disease, neuroprotection, and neurodegenerative diseases such as stroke and Alzheimer's disease (1-6). However, the Women's Health Initiative (WHI) surprisingly failed to observe a protective effect of hormone therapy on the cardiovascular system and, in fact, reported a small but significant increase in risk for stroke and dementia (7-9). The average age of subjects in the WHI study was 63 y, far past the onset of menopause. It has been suggested that there may be a "critical period" for the beneficial protective effect of E2 on the brain and that estrogen may need to be administered at perimenopause or earlier to observe a beneficial effect on the cardiovascular and neural system (10-12). In support of a critical period hypothesis for E2 beneficial effects in the brain, work by our laboratory and others has shown that long-term E2 deprivation (LTED) leads to a loss of E2 neuroprotection in animal models of focal and global cerebral ischemia (GCI) (13,14). Intriguingly, recent work by our group showed that the loss of E2 neuroprotection of the hippocampal CA1 region, an area ...

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Section: Discussionsupporting

confidence: 92%

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

Zhang

Han

Wang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

127

132

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“…This finding is consistent with previous reports in OVX rodents. 8,9,21 By contrast, G-1 treatment had no effect on stroke outcome in intact females, in which GPER occupancy would presumably be opposed by high levels of circulating and bound estrogen, analogous to observations that estrogen supplementation has little or no neuroprotective effects after stroke in intact females. 22 These findings highlight the complex nature of endogenous estrogen signaling, which may involve 3 receptor types and vary between different physiological and disease settings, and they reinforce the body of evidence indicating that effects of estrogen in the female brain are not necessarily transferrable to males.…”

Section: Strokementioning

confidence: 66%

Sex-Dependent Effects of G Protein–Coupled Estrogen Receptor Activity on Outcome After Ischemic Stroke

Broughton

Brait

Kim

et al. 2014

Stroke

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O ur knowledge of estrogen signaling pathways during cerebral ischemia, including the relative importance of different estrogen receptors and identities of estrogen-regulated gene networks affecting neuronal death, remains incomplete. Until recently, estrogen was thought to elicit its neuroprotective actions solely via activation of the classical nuclear receptors, estrogen receptor(ER)α and ERβ.1,2 However, the discovery of a novel estrogen receptor called G protein-coupled estrogen receptor (GPER, formerly known as GPR30), with high expression in the brain 3,4 and cerebral circulation, 5 presents a third receptor that may influence estrogenmediated outcomes after stroke. Important differences exist between GPER and classical estrogen receptors in that GPER responds to estrogen with rapid cellular signaling, and it is a G protein-coupled receptor localized on the plasma membrane 6 and intracellular membranes such as the endoplasmic reticulum and Golgi apparatus. Similar to classical estrogen receptor signaling, there is evidence for neuroprotection after GPER activation in ovariectomized (OVX) animals subjected to stroke. Chronic pretreatment of OVX rodents with the selective GPER agonist, G-1, reduces brain injury after focal or global ischemia. 8,9Interestingly, we have found that GPER distribution and expression is increased in the brain of male mice, but not of intact female or OVX mice, after transient focal ischemia. 4This sex-dependent regulation of GPER expression after cerebral ischemia could help explain some of the complex effects of estrogen in the brain after stroke and also guide the Background and Purpose-Experimental studies indicate that estrogen typically, but not universally, has a neuroprotective effect in stroke. Ischemic stroke increases membrane-bound G protein-coupled estrogen receptor (GPER) distribution and expression in the brain of male but not female mice. We hypothesized that GPER activation may have a greater neuroprotective effect in males than in females after stroke. Methods-Vehicle (dimethyl sulfoxide), a GPER agonist (G-1, 30 μg/kg), or a GPER antagonist (G-15, 300 μg/kg) were administered alone or in combination to young or aged male mice, or young intact or ovariectomized female mice, 1 hour before or 3 hours after cerebral ischemia-reperfusion. Some mice were treated with a combination of G-1 and the pancaspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-V D -OPh), 1 hour before stroke. We evaluated functional and histological end points of stroke outcome up to 72 hours after ischemia-reperfusion. In addition, apoptosis was examined using cleaved caspase-3 immunohistochemistry. Results-Surprisingly, G-1 worsened functional outcomes and increased infarct volume in males poststroke, in association with an increased expression of cleaved caspase-3 in peri-infarct neurons. These effects were blocked by G-15 or Q-VDOPh. Conversely, G-15 improved functional outcomes and reduced infarct volume after stroke in males, whether given before or after stroke. In contrast to find...

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“…Through genomic and nongenomic mechanisms, E2 modulates neuronal excitability and rapidly increases signal transmission by regulating both NMDA and non-NMDA glutamate receptors (NMDARs) (Wong and Moss, 1992;Foy et al, 1999). The GPR30 receptor may act together with intracellular estrogen receptors to activate cell-signaling pathways to promote neuron survival after global ischemia (Hazell et al, 2009;Gingerich et al, 2010;Lebesgue et al, 2010). However, the role of GPR30 in neuroprotection against excitotoxic neuronal death induced by NMDA exposure remains unknown.…”

Section: Introductionmentioning

confidence: 99%

G-Protein-Coupled Receptor 30 Mediates Rapid Neuroprotective Effects of Estrogen via Depression of NR2B-Containing NMDA Receptors

Liu

Zhang²,

Guo³

et al. 2012

J. Neurosci.

145

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17-␤-Estradiol (E2)is a steroid hormone involved in neuroprotection against excitotoxicity and other forms of brain injury. Through genomic and nongenomic mechanisms, E2 modulates neuronal excitability and signal transmission by regulating NMDA and non-NMDA receptors. However, the mechanisms and identity of the receptors involved remain unclear, even though studies have suggested that estrogen G-protein-coupled receptor 30 (GPR30) is linked to protection against ischemic injury. In the culture cortical neurons, treatment with E2 and the GPR30 agonist G1 for 45 min attenuated the excitotoxicity induced by NMDA exposure. The acute neuroprotection mediated by GPR30 is dependent on G-protein-coupled signals and ERK1/2 activation, but independent on transcription or translation. Knockdown of GPR30 using short hairpin RNAs (shRNAs) significantly reduced the E2-induced rapid neuroprotection. Patch-clamp recordings revealed that GPR30 activation depressed exogenous NMDA-elicited currents. Short-term GPR30 activation did not affect the expression of either NR2A-or NR2B-containing NMDARs; however, it depressed NR2B subunit phosphorylation at Ser-1303 by inhibiting the dephosphorylation of death-associated protein kinase 1 (DAPK1). DAPK1 knockdown using shRNAs significantly blocked NR2B subunit phosphorylation at Ser-1303 and abolished the GPR30-mediated depression of exogenous NMDA-elicited currents. Lateral ventricle injection of the GPR30 agonist G1 (0.2 g) provided significant neuroprotection in the ovariectomized female mice subjected to middle cerebral artery occlusion. These findings provide direct evidence that fast neuroprotection by estradiol is partially mediated by GPR30 and the subsequent downregulation of NR2B-containing NMDARs. The modulation of DAPK1 activity by GPR30 may be an important mediator of estradiol-dependent neuroprotection.

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Acute Administration of Non-Classical Estrogen Receptor Agonists Attenuates Ischemia-Induced Hippocampal Neuron Loss in Middle-Aged Female Rats

Cited by 136 publications

References 54 publications

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

Sex-Dependent Effects of G Protein–Coupled Estrogen Receptor Activity on Outcome After Ischemic Stroke

G-Protein-Coupled Receptor 30 Mediates Rapid Neuroprotective Effects of Estrogen via Depression of NR2B-Containing NMDA Receptors

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