Neuroprotection against excitotoxic brain injury in mice after ovarian steroid depletion

Ovarian steroid hormones influence not only seizure phenomena, but also the neuronal cell death that follows. In the present study, we applied two models of ovarian steroid loss, ovariectomy and chemically-induced ovarian failure, to evaluate kainate-induced seizure activity and the susceptibility of hippocampal neurons to seizure-induced neurodegeneration. Young adult female FVB/NJ mice were ovariectomized with (OVX+E, n = 6) or without (OVX, n = 8) estrogen replacement. A separate group of females received the ovotoxin, 4-vinylcyclohexene diepoxide (VCD, n = 8) to deplete ovarian follicles. Mice underwent kainate-induced status epilepticus and were evaluated for seizure activity (3 h) and delayed hippocampal neuronal injury (7 days). While there were no differences in latency or duration of severe seizures among control, OVX and VCD-treated mice, OVX+E mice exhibited seizures of a significantly longer duration. However, both VCD-induced ovarian failure and OVX led to a dramatic reduction in the extent of excitotoxic cell death, with slightly greater effects observed in VCD-treated mice. Estradiol administration to OVX mice also exerted a significant neuroprotective effect against kainate-induced cell death. These results support and extend earlier findings suggesting that the hormonal milieu may have differential effects on seizure susceptibility that are separate and distinct from those influencing hippocampal neuronal vulnerability. Collectively, these findings highlight the complex interactions among the loss of ovarian steroid hormones, estrogen replacement, seizures, and seizure-induced cell death.