Estrogen treatment offers neuro-protection in animal experiments in which excitotoxic mechanisms destroy neurons. In a model of delayed neuronal degeneration that depends on excitotoxicity, we tested whether females had an altered susceptibility, and whether physiologic doses of estrogen administered after the brain insult would protect susceptible neurons. Females were ovariectomized, exposed to striatal-pallidal ibotenic acid injury that caused delayed degeneration of substantia nigra neurons, and treated with 17 beta -estradiol (30 microg, subcutaneously every other day, beginning 2 days after the striatal injury) or vehicle. At 6 and 8 days post lesion, the 17beta-estradiol treatment group maintained over 87 and 70% of control nigral neuron number, respectively. Physiologic levels of estrogen delivered days after the excitotoxic stress completely protected neurons in the substantia nigra reticulata 6 days post lesion and slowed degeneration 8 days post lesion.