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Chronic but not acute estradiol treatment protects against the neurodegenerative effects of N-methyl-d-aspartate receptor antagonists

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Abstract

Drugs that block NMDA receptors, thereby inducing an NMDA receptor hypofunctional (NRHypo) state, can cause a disseminated pattern of irreversible neurodegeneration. Based on several lines of evidence, an N-methyl-d-aspartate receptor hypofunction (NRHypo) mechanism has been postulated to contribute to neurodegenerative changes in Alzheimer disease (AD). Because estrogen putatively exerts a neuroprotective effect in AD, we examined whether estrogen protects against NRHypo-induced neurodegeneration. We administered estradiol benzoate in three separate experiments to adult female rats: (1) 100 µg subcutaneously as a onetime dose, (2) 100 µg bid twice daily for 4.5 or 14 d, and 3) 300 µg twice daily for 4.5 d. Two hours after the last estradiol dose, MK-801 was administered (0.5 mg/kg subcutaneously) to produce a robust neurotoxic injury. Controls received MK-801, but no estradiol. Four hours after administration of MK-801, the severity of injury was evaluated histologically by quantitative methods previously described. Compared to controls, a single dose of estradiol produced no change in the severity of injury (p=0.24). Chronic treatment with estradiol was associated with a 25–35% reduction in the number of injured neurons (p<0.05 in all cases). We conclude that chronic but not acute estradiol treatment reduces the severity of NRHypo-induced neurodegeneration.

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Authors and Affiliations

  1. Department of Psychiatry, Washington University, St. Louis, MO

    William H. Dribben, Brian M. Nemmers, Anthony R. Nardi, John W. Olney & Nuri B. Farber

  2. Division of Emergency Medicine, Washington University, St. Louis, MO

    William H. Dribben

  3. Department of Psychology, University of Missouri, St. Louis, MO

    George T. Taylor

Authors
  1. William H. Dribben
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  2. Brian M. Nemmers
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  3. Anthony R. Nardi
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  4. George T. Taylor
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  5. John W. Olney
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  6. Nuri B. Farber
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Correspondence to William H. Dribben.

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Dribben, W.H., Nemmers, B.M., Nardi, A.R. et al. Chronic but not acute estradiol treatment protects against the neurodegenerative effects of N-methyl-d-aspartate receptor antagonists. Endocr 21, 53–58 (2003). https://doi.org/10.1385/ENDO:21:1:53

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  • DOI: https://doi.org/10.1385/ENDO:21:1:53

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