Chronic but not acute estradiol treatment protects against the neurodegenerative effects of N-methyl-D-aspartate receptor antagonists.
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 microg subcutaneously as a onetime dose, (2) 100 microg bid twice daily for 4.5 or 14 d, and 3) 300 microg 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.
Dribben
William
W
Department of Psychiatry, Division of Emergency Medicine, Washington University, St. Louis, MO 63110, USA. dribbenw@msnotes.wustl.edu
Nemmers
Brian
B
Nardi
Anthony
A
Taylor
George
G
Olney
John
J
Farber
Nuri
N
D000818:Animals; D001921:Brain / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D004958:Estradiol; D016291:Dizocilpine Maleate