Abstracts

Rationale: Studies have shown that women who suffer from epilepsy have varying susceptibility to seizures during times when their hormone levels fluctuate, such as the menstrual cycle. In addition to monthly hormonal changes, there is another essential point in a woman’s lifetime where hormones radically fluctuate and then eventually decline, a stage we refer to as menopause. Though studies have demonstrated that hormones can be both neuroprotective and epileptogenic, it remains unclear how declining levels of steroid hormones can modify the course of epilepsy in women undergoing reproductive senescence. As equally unclear are the beneficial or detrimental effects hormone replacement therapy (HRT) may have on epileptic women who undergo menopause.Methods: Female FVB/NJ (FVB) mice were injected with the excitotoxin, kainic acid (KA). Four weeks following KA injections, and after visual confirmation of spontaneous recurrent seizures, mice were injected with VCD, an ovotoxin, and control mice were injected with vehicle. Another set of epileptic mice were treated similar to the first group, but were simultaneously implanted with an estrogen pellet (Eβ) to simulate HRT. Four weeks following these treatments, brains were processed for microscopic analysis to assess the amount of seizure induced-cell death and mossy fiber sprouting.Results: In the first set of experiments, epileptic mice that were treated with VCD showed a significant amount of neuroprotection against seizure-induced cell death, as compared to vehicle treated mice (VEH). In addition, VCD treated mice also showed a dramatic reduction in the amount of mossy fiber sprouting. For the second group of epileptic mice, both the VCD + Eβ and the vehicle + Eβ groups showed a significant increase in the amount of hippocampal cell loss, as compared to the mice treated with VCD alone but not statistically significant to each other. It is also important to note that VCD + Eβ mice still showed a substantial reduction in cell death as compared to VEH. We saw a similar result for mossy fiber sprouting where the VCD + Eβ and vehicle + Eβ mice exhibited a greater mount of mossy fiber sprouting as compared to the epileptic mice treated with only VCD. Again, while not statistically significant to the VCD + Eβ treated mice, mice treated with vehicle + Eβ had the largest amount of mossy fiber sprouting.Conclusions: These results suggest a strong modulatory role of reproductive hormones on the kainate model of epilepsy. Not only do these results support estrogen as a neuroprotectant it also indicates that estrogen has deleterious effects on mossy fiber sprouting by acting as a trophic factor. Because these results provide compelling evidence that menopause alters the course of epilepsy, it will be essential in future studies to tease apart specific effects of reproductive hormones in order to determine an appropriate course of treatment for menopausal women with epilepsy.