Extranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus.
dc.contributor.author | Yang, Li-cai | |
dc.contributor.author | Zhang, Quan-Guang | |
dc.contributor.author | Zhou, Cai-feng | |
dc.contributor.author | Yang, Fang | |
dc.contributor.author | Zhang, Yi-dong | |
dc.contributor.author | Wang, Rui-min | |
dc.contributor.author | Brann, Darrell W | |
dc.date.accessioned | 2010-09-24T21:26:46Z | |
dc.date.available | 2010-09-24T21:26:46Z | |
dc.date.issued | 2010-05-18 | en_US |
dc.identifier.citation | PLoS One. 2010 May 7; 5(5):e9851 | en_US |
dc.identifier.issn | 1932-6203 | en_US |
dc.identifier.pmid | 20479872 | en_US |
dc.identifier.doi | 10.1371/journal.pone.0009851 | en_US |
dc.identifier.uri | http://hdl.handle.net/10675.2/47 | |
dc.description.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. | |
dc.rights | The 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.mesh | Animals | en_US |
dc.subject.mesh | Brain Ischemia / enzymology / pathology | en_US |
dc.subject.mesh | Brain-Derived Neurotrophic Factor / metabolism | en_US |
dc.subject.mesh | CA1 Region, Hippocampal / drug effects / enzymology / pathology | en_US |
dc.subject.mesh | Cell Membrane / drug effects / metabolism | en_US |
dc.subject.mesh | Cell Nucleus / drug effects / metabolism | en_US |
dc.subject.mesh | Cell Survival / drug effects | en_US |
dc.subject.mesh | Cognition / drug effects | en_US |
dc.subject.mesh | Cyclic AMP Response Element-Binding Protein / metabolism | en_US |
dc.subject.mesh | Dendrimers / pharmacology | en_US |
dc.subject.mesh | Estradiol / metabolism / pharmacology | en_US |
dc.subject.mesh | Estrogens / pharmacology | en_US |
dc.subject.mesh | Estrogens, Conjugated (USP) / pharmacology | en_US |
dc.subject.mesh | Extracellular Signal-Regulated MAP Kinases / metabolism | en_US |
dc.subject.mesh | Female | en_US |
dc.subject.mesh | Hippocampus / drug effects / metabolism | en_US |
dc.subject.mesh | Injections, Intraventricular | en_US |
dc.subject.mesh | JNK Mitogen-Activated Protein Kinases / metabolism | en_US |
dc.subject.mesh | MAP Kinase Signaling System / drug effects | en_US |
dc.subject.mesh | Neurons / drug effects / enzymology / pathology | en_US |
dc.subject.mesh | Neuroprotective Agents / pharmacology | en_US |
dc.subject.mesh | Phosphorylation / drug effects | en_US |
dc.subject.mesh | Rats | en_US |
dc.subject.mesh | Rats, Sprague-Dawley | en_US |
dc.subject.mesh | Receptors, Estrogen / metabolism | en_US |
dc.subject.mesh | Serum Albumin, Bovine / metabolism / pharmacology | en_US |
dc.title | Extranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus. | en_US |
dc.type | Journal Article | en_US |
dc.type | Research Support, N.I.H., Extramural | en_US |
dc.type | Research Support, Non-U.S. Gov't | en_US |
dc.identifier.pmcid | PMC2866326 | en_US |
dc.contributor.corporatename | Institute of Molecular Medicine and Genetics | en_US |
refterms.dateFOA | 2019-04-09T21:00:11Z | |
html.description.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. |