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 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.