Extranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus.

Hdl Handle:
http://hdl.handle.net/10675.2/47
Title:
Extranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus.
Authors:
Yang, Li-cai; Zhang, Quan-Guang; Zhou, Cai-feng; Yang, Fang; Zhang, Yi-dong; Wang, Rui-min; Brann, Darrell W ( 0000-0002-4480-8859 )
Abstract:
BACKGROUND: 17beta-estradiol (E2) has been implicated to exert neuroprotective effects in the brain following cerebral ischemia. Classically, E2 is thought to exert its effects via genomic signaling mediated by interaction with nuclear estrogen receptors. However, the role and contribution of extranuclear estrogen receptors (ER) is unclear and was the subject of the current study. METHODOLOGY/PRINCIPAL FINDINGS: To accomplish this goal, we employed two E2 conjugates (E2 dendrimer, EDC, and E2-BSA) that can interact with extranuclear ER and exert rapid nongenomic signaling, but lack the ability to interact with nuclear ER due to their inability to enter the nucleus. EDC or E2-BSA (10 microM) was injected icv 60 min prior to global cerebral ischemia (GCI). FITC-tagged EDC or E2-BSA revealed high uptake in the hippocampal CA1 region after icv injection, with a membrane (extranuclear) localization pattern in cells. Both EDC and E2-BSA exerted robust neuroprotection in the CA1 against GCI, and the effect was blocked by the ER antagonist, ICI182,780. EDC and E2-BSA both rapidly enhanced activation of the prosurvival kinases, ERK and Akt, while attenuating activation of the proapoptotic kinase, JNK following GCI, effects that were blocked by ICI182,780. Administration of an MEK or PI3K inhibitor blocked the neuroprotective effects of EDC and E2-BSA. Further studies showed that EDC increased p-CREB and BDNF in the CA1 region in an ERK- and Akt-dependent manner, and that cognitive outcome after GCI was preserved by EDC in an ER-dependent manner. CONCLUSIONS/SIGNIFICANCE: In conclusion, the current study demonstrates that activation of extranuclear ER results in induction of ERK-Akt-CREB-BDNF signaling in the hippocampal CA1 region, which significantly reduces ischemic neuronal injury and preserves cognitive function following GCI. The study adds to a growing literature that suggests that extranuclear ER can have important actions in the brain.
Citation:
PLoS One. 2010 May 7; 5(5):e9851
Issue Date:
18-May-2010
URI:
http://hdl.handle.net/10675.2/47
DOI:
10.1371/journal.pone.0009851
PubMed ID:
20479872
PubMed Central ID:
PMC2866326
Type:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
ISSN:
1932-6203
Appears in Collections:
Institute of Molecular Medicine and Genetics: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorYang, Li-caien_US
dc.contributor.authorZhang, Quan-Guangen_US
dc.contributor.authorZhou, Cai-fengen_US
dc.contributor.authorYang, Fangen_US
dc.contributor.authorZhang, Yi-dongen_US
dc.contributor.authorWang, Rui-minen_US
dc.contributor.authorBrann, Darrell Wen_US
dc.date.accessioned2010-09-24T21:26:46Z-
dc.date.available2010-09-24T21:26:46Z-
dc.date.issued2010-05-18en_US
dc.identifier.citationPLoS One. 2010 May 7; 5(5):e9851en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid20479872en_US
dc.identifier.doi10.1371/journal.pone.0009851en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/47-
dc.description.abstractBACKGROUND: 17beta-estradiol (E2) has been implicated to exert neuroprotective effects in the brain following cerebral ischemia. Classically, E2 is thought to exert its effects via genomic signaling mediated by interaction with nuclear estrogen receptors. However, the role and contribution of extranuclear estrogen receptors (ER) is unclear and was the subject of the current study. METHODOLOGY/PRINCIPAL FINDINGS: To accomplish this goal, we employed two E2 conjugates (E2 dendrimer, EDC, and E2-BSA) that can interact with extranuclear ER and exert rapid nongenomic signaling, but lack the ability to interact with nuclear ER due to their inability to enter the nucleus. EDC or E2-BSA (10 microM) was injected icv 60 min prior to global cerebral ischemia (GCI). FITC-tagged EDC or E2-BSA revealed high uptake in the hippocampal CA1 region after icv injection, with a membrane (extranuclear) localization pattern in cells. Both EDC and E2-BSA exerted robust neuroprotection in the CA1 against GCI, and the effect was blocked by the ER antagonist, ICI182,780. EDC and E2-BSA both rapidly enhanced activation of the prosurvival kinases, ERK and Akt, while attenuating activation of the proapoptotic kinase, JNK following GCI, effects that were blocked by ICI182,780. Administration of an MEK or PI3K inhibitor blocked the neuroprotective effects of EDC and E2-BSA. Further studies showed that EDC increased p-CREB and BDNF in the CA1 region in an ERK- and Akt-dependent manner, and that cognitive outcome after GCI was preserved by EDC in an ER-dependent manner. CONCLUSIONS/SIGNIFICANCE: In conclusion, the current study demonstrates that activation of extranuclear ER results in induction of ERK-Akt-CREB-BDNF signaling in the hippocampal CA1 region, which significantly reduces ischemic neuronal injury and preserves cognitive function following GCI. The study adds to a growing literature that suggests that extranuclear ER can have important actions in the brain.en_US
dc.rightsThe PMC Open Access Subset is a relatively small part of the total collection of articles in PMC. Articles in the PMC Open Access Subset are still protected by copyright, but are made available under a Creative Commons or similar license that generally allows more liberal redistribution and reuse than a traditional copyrighted work. Please refer to the license statement in each article for specific terms of use. The license terms are not identical for all articles in this subset.en_US
dc.subject.meshAnimalsen_US
dc.subject.meshBrain Ischemia / enzymology / pathologyen_US
dc.subject.meshBrain-Derived Neurotrophic Factor / metabolismen_US
dc.subject.meshCA1 Region, Hippocampal / drug effects / enzymology / pathologyen_US
dc.subject.meshCell Membrane / drug effects / metabolismen_US
dc.subject.meshCell Nucleus / drug effects / metabolismen_US
dc.subject.meshCell Survival / drug effectsen_US
dc.subject.meshCognition / drug effectsen_US
dc.subject.meshCyclic AMP Response Element-Binding Protein / metabolismen_US
dc.subject.meshDendrimers / pharmacologyen_US
dc.subject.meshEstradiol / metabolism / pharmacologyen_US
dc.subject.meshEstrogens / pharmacologyen_US
dc.subject.meshEstrogens, Conjugated (USP) / pharmacologyen_US
dc.subject.meshExtracellular Signal-Regulated MAP Kinases / metabolismen_US
dc.subject.meshFemaleen_US
dc.subject.meshHippocampus / drug effects / metabolismen_US
dc.subject.meshInjections, Intraventricularen_US
dc.subject.meshJNK Mitogen-Activated Protein Kinases / metabolismen_US
dc.subject.meshMAP Kinase Signaling System / drug effectsen_US
dc.subject.meshNeurons / drug effects / enzymology / pathologyen_US
dc.subject.meshNeuroprotective Agents / pharmacologyen_US
dc.subject.meshPhosphorylation / drug effectsen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Sprague-Dawleyen_US
dc.subject.meshReceptors, Estrogen / metabolismen_US
dc.subject.meshSerum Albumin, Bovine / metabolism / pharmacologyen_US
dc.titleExtranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, N.I.H., Extramuralen_US
dc.typeResearch Support, Non-U.S. Gov'ten_US
dc.identifier.pmcidPMC2866326en_US
dc.contributor.corporatenameInstitute of Molecular Medicine and Geneticsen_US
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