Abstracts

Studies have shown a correlation between estrous cycle and seizure susceptibility in humans and most mammals. This effect is also seen during menopause, or reproductive senescence. It has been hypothesized that the hormonal fluctuations throughout the various stages of estrous exert some type of influence on seizure occurrence, prevalence, and severity. The goal of this study was to analyze the effect of ovarian hormone cyclicity at different stages of estrous, the loss of ovarian hormones and the relationship to kainate-induced seizure susceptibility and seizure induced cell death., Control female mice of the FVB/NJ (FVB) strain were administered kainic acid (KA) at different stages of the estrous cycle. Estrous cycle was determined by vaginal cytology and only regularly cycling animals were chosen for the experiments. KA or saline was administered systemically to female FVB mice at various stages of the estrous cycle, to ovariectomized (OVX) females, OVX females treated with estradiol (OVX + E), and VCD-treated female mice. Mice were monitored for 4 hours for seizure onset, severity, and activity and scored for latency to onset of first severe seizure and duration of severe seizures. After 7 days of recovery, neuronal damage was evaluated throughout the hippocampus proper., Among ovary-intact female FVB mice, estrous cyclicity was without effect on seizure susceptibility. In particular, no significant differences in latency to onset or duration of severe seizures were noted. In contrast, in the OVX + E female mice, seizure duration was significantly increased, and latency to onset of seizures was reduced, as compared to OVX and ovary-intact female mice. The extent of hippocampal cell death among ovary-intact mice was not affected based on estrous cycle staging. In particular, no significant differences in the extent of cell death were observed between ovary-intact female FVB mice injected with KA during estrus, when gonadal hormone levels peak, or during diestrus, the nadir of gonadal hormone levels., Our results suggest that estradiol may lower the threshold for seizure activity. While we found no modulatory effects of estradiol on seizure susceptibility or cell death based on estrous cyclicity, it is important to note that two different models for the modulation of ovarian steroid levels were used. In one model, ovariectomy (OVX) causes a complete disruption of gonadal hormones. In contrast, ovarian steroid levels vary across the estrous cycle in ovary-intact female mice. In addition, OVX + E mice have none of the protective effects of progesterone present. Studies are ongoing to compare two models of reproductive senescence: the OVX model and the chemically-induced VCD model. Insight into the mechanisms of brain related-changes as a result of the loss of ovarian steroids will help identify risk factors for seizure susceptibility and cell death in aging women.,