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The Journal of Neuroscience, June 15, 2003, 23(12):4984-4995

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Estrogens and ICI182,780 (Faslodex) Modulate Mitosis and Cell Death in Immature Cerebellar Neurons via Rapid Activation of p44/p42 Mitogen-Activated Protein Kinase

Jeremy K. Wong,² Hoa H. Le,¹ Attila Zsarnovszky,¹ and Scott M. Belcher^1,2

¹Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0575, and ²Interdisciplinary Toxicology Graduate Program, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

Estrogen influences the development and function of the nervous system through estrogen receptor-dependent changes in gene expression and by rapidly influencing diverse intracellular signaling pathways. We have investigated the influence of estradiol on developing neonatal rat cerebellar neurons in primary culture and found that low concentrations of 17-estradiol (17-E₂), 17-E₂, 17-E₂-BSA, and ICI182,780 stimulated phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) mitogen-activated protein kinases (MAPK). Neither testosterone nor progesterone increased ERK1/2 phosphorylation. The effects of the estrogens were specific to the ERK1/2 MAPK pathway and were blocked by U0126, an inhibitor of the ERK1/2 MAPK kinase (MEK1/2). Compared with control cultures, significant MAPK-dependent decreases in viable granule cell numbers were observed in dissociated explant cultures of developing cerebellar neurons 24–96 hr after pulse treatment with 10 pM 17-E₂ or 10 nM ICI182,780. In contrast, continuous exposure to 10 pM 17-E₂ significantly increased granule cell numbers. Analysis of bromodeoxyuridine incorporation revealed that a 15 min pulsed treatment with 10 pM 17-E₂ increased mitogenesis, whereas continuous exposure to the same concentration of 17-E₂ was anti-mitotic. Estradiol did not increase caspase activity; however, significant increases in cellular permeability and lysis were observed. Cell lysis and death were independent of the pan-caspase inhibitor zVAD-fmk but were blocked fully by the irreversible calpain inhibitor PD150606. These results indicate that rapid activation of the ERK1/2 MAPK pathway by low concentrations of 17-E₂ induces oncotic/necrotic, but not apoptotic, programmed cell death in a subpopulation of developing granule cells and increased mitogenesis of the granule cell neuroblasts refractory to estrogen-induced neurotoxicity.

Key words: cerebellum; development; ERK; estradiol; estrogen; granule cell; MAPK; necrosis; neuron; neurotoxicity; oncosis

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Received Jan. 3, 2003; revised Mar. 21, 2003; accepted Mar. 21, 2003.

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