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The Journal of Neuroscience, August 3, 2005, 25(31):7191-7198; doi:10.1523/JNEUROSCI.1328-05.2005

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Cellular/Molecular
Role of Protein Phosphatases in Estrogen-Mediated Neuroprotection

Kun Don Yi, Jaegwon Chung, Priscilla Pang, and James W. Simpkins

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas 76107

The signaling pathways that mediate neurodegeneration are complex and involve a balance between phosphorylation and dephosphorylation of signaling and structural proteins. We have shown previously that 17-estradiol and its analogs are potent neuroprotectants. The purpose of this study was to delineate the role of protein phosphatases (PPs) in estrogen neuroprotection against oxidative stress and excitotoxicity. HT-22 cells, C6-glioma cells, and primary rat cortical neurons were exposed to the nonspecific serine/threonine protein phosphatase inhibitors okadaic acid and calyculin A at various concentrations in the presence or absence of 17-estradiol and/or glutamate. Okadaic acid and calyculin A caused a dose-dependent decrease in cell viability in HT-22, C6-glioma, and primary rat cortical neurons. 17-Estradiol did not show protection against neurotoxic concentrations of either okadaic acid or calyculin A in these cells. In the absence of these serine/threonine protein phosphatase inhibitors, 17-estradiol attenuated glutamate toxicity. However, in the presence of effective concentrations of these protein phosphatase inhibitors, 17-estradiol protection against glutamate toxicity was lost. Furthermore, glutamate treatment in HT-22 cells and primary rat cortical neurons caused a 50% decrease in levels of PP1, PP2A, and PP2B protein, whereas coadministration of 17-estradiol with glutamate prevented the decrease in PP1, PP2A, and PP2B levels. These results suggest that 17-estradiol may protect cells against glutamate-induced oxidative stress and excitotoxicity by activating a combination of protein phosphatases.

Key words: estrogen; neuroprotection; phosphatases; neurotoxicity; glutamate; neuronal death

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Received April 6, 2005; revised June 17, 2005; accepted June 22, 2005.

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