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

Li Cai Yang, Quanguang Zhang, Cai Feng Zhou, Fang Yang, Yi Dong Zhang, Rui Min Wang, Darrell W Brann

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Background: 17b-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 μM) 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.

Original languageEnglish (US)
Article numbere9851
JournalPLoS One
Volume5
Issue number5
DOIs
StatePublished - Sep 17 2010

Fingerprint

neuroprotective effect
Neuroprotective Agents
hippocampus
Estrogen Receptors
estrogens
Rats
Brain Ischemia
Hippocampus
Estrogens
ischemia
rats
mitogen-activated protein kinase
Hippocampal CA1 Region
Chemical activation
Brain-Derived Neurotrophic Factor
Brain
MAP Kinase Kinase 4
phosphotransferases (kinases)
Dendrimers
Aptitude

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Extranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus. / Yang, Li Cai; Zhang, Quanguang; Zhou, Cai Feng; Yang, Fang; Zhang, Yi Dong; Wang, Rui Min; Brann, Darrell W.

In: PLoS One, Vol. 5, No. 5, e9851, 17.09.2010.

Research output: Contribution to journalArticle

Yang, Li Cai ; Zhang, Quanguang ; Zhou, Cai Feng ; Yang, Fang ; Zhang, Yi Dong ; Wang, Rui Min ; Brann, Darrell W. / Extranuclear estrogen receptors mediate the neuroprotective effects of estrogen in the rat hippocampus. In: PLoS One. 2010 ; Vol. 5, No. 5.
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abstract = "Background: 17b-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 μM) 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.",
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AU - Yang, Li Cai

AU - Zhang, Quanguang

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AU - Wang, Rui Min

AU - Brann, Darrell W

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