Estrogen protects primary cortical neurons from glutamate neurotoxicity

Estrogens have been shown to exert neurotrophic effects in the brain by regulating processes involved in neuronal growth, differentiation and survival. The ability of estrogen to promote neuronal survival has been shown in primary neuronal cultures from the amygdala, as well as in neuroblastoma and glial cells during serum deprivation or hypoglycemia. This leads to the possibility that estrogen might exert neuroprotective effects during other types of cytotoxic insults. Neurotoxicity mediated by the excitatory neurotransmitter glutamate has been extensively studied in primary cortical neurons and the present experiments were designed to examine the possibility that estrogen may protect these neurons from glutamate neurotoxicity. Rat primary cortical neurons were cultured for 7 to 12 days in a serum-containing medium. Twenty-four h prior to glutamate exposure, the cells were shifted to a serum-free medium containing various concentrations of 17-estradiol, 17a-estradiol or cholesterol. The neurons were then exposed to 50 μM or 100 μM glutamate for 5 min and maintained in a serum-free medium prior to assay. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) in the medium 24 h after glutamate exposure. Results from these experiments demonstrated that 10 nM 17β-estradiol protects cortical neurons from exposure to glutamate. Treatment with 10 nM 17α-estradiol or 10 nM of the steroid precursor cholesterol did not protect the neurons. These results demonstrate that 17β-estradiol can protect neurons from glutamate toxicity. The molecular basis of this protective effect, however, remains to be elucidated.