MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia

Teresa Jover-Mengual, R. Suzanne Zukin, Anne M. Etgen

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal womenremains controversial. Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which estrogens intervene in global ischemia-induced apoptotic cell death are unclear. Here we show that estradiol acts via the classical estrogen receptors, the IGF-I receptor, and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global ischemia promotes early dephosphorylation and inactivation of ERK1 and the transcription factor cAMP-response element binding protein (CREB), subsequent down-regulation of the antiapoptotic protein Bcl-2, a known gene target of estradiol and CREB, and activation of caspase-3. Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, down-regulation of Bcl-2 and activation of the caspase death cascade. Whereas ERK/MAPK signaling is critical toCREBactivation and neuronal survival, the impact of estradiol on Bcl-2 levels is ERK independent. These findings support a model whereby estradiol acts via the classical estrogen receptors and IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global ischemia.

Original languageEnglish (US)
Pages (from-to)1131-1143
Number of pages13
JournalEndocrinology
Volume148
Issue number3
DOIs
StatePublished - Mar 2007

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Estradiol
Ischemia
Cyclic AMP Response Element-Binding Protein
IGF Type 1 Receptor
Estrogen Receptors
Down-Regulation
Caspase 2
Neurons
Gerbillinae
Neuroprotection
Heart Arrest
Caspase 3
Thoracic Surgery
Rodentia
Estrogens
Cell Death
Transcription Factors
Phosphorylation
Hormones
Genes

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia. / Jover-Mengual, Teresa; Zukin, R. Suzanne; Etgen, Anne M.

In: Endocrinology, Vol. 148, No. 3, 03.2007, p. 1131-1143.

Research output: Contribution to journalArticle

Jover-Mengual, Teresa ; Zukin, R. Suzanne ; Etgen, Anne M. / MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia. In: Endocrinology. 2007 ; Vol. 148, No. 3. pp. 1131-1143.
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