This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jover-Mengual, T. Articles by Etgen, A. M. Search for Related Content PubMed PubMed Citation Articles by Jover-Mengual, T. Articles by Etgen, A. M.

MAPK Signaling Is Critical to Estradiol Protection of CA1 Neurons in Global Ischemia

Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Address all correspondence and requests for reprints to: Dr. Anne M. Etgen, Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461. E-mail: etgen{at}aecom.yu.edu.

The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal women remains 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 to CREB activation 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.

This article has been cited by other articles:

				E.-S. Y. Lee, Z. Yin, D. Milatovic, H. Jiang, and M. Aschner Estrogen and Tamoxifen Protect against Mn-Induced Toxicity in Rat Cortical Primary Cultures of Neurons and Astrocytes Toxicol. Sci., July 1, 2009; 110(1): 156 - 167. [Abstract] [Full Text] [PDF]

				L. A. Tremere, J. K. Jeong, and R. Pinaud Estradiol Shapes Auditory Processing in the Adult Brain by Regulating Inhibitory Transmission and Plasticity-Associated Gene Expression J. Neurosci., May 6, 2009; 29(18): 5949 - 5963. [Abstract] [Full Text] [PDF]

				M. P. Hutchens, J. Dunlap, P. D. Hurn, and P. O. Jarnberg Renal Ischemia: Does Sex Matter? Anesth. Analg., July 1, 2008; 107(1): 239 - 249. [Abstract] [Full Text] [PDF]