April Levin

Date of Award

3-4-2008

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Hal Blumenfeld

Abstract

The purpose of this study was to determine how early seizure blockade with ethosuximide (ESX) would influence ion channel expression and long-term spike-wave discharge (SWD) activity in epileptic WAG/Rij rats. The goal was to elucidate the question Do seizures beget seizures? in a genetically prone model and if so, to attempt to interrupt this cycle by early intervention. In our first experiment, we used immunocytochemistry to determine the effect of ESX on cortical expression of ion channels in treated and untreated WAG/Rij rats and age-matched Wistar controls. This experiment revealed that treatment with ESX blocked the upregulation of Nav1.1 and Nav1.6 as well as the downregulation of HCN1 that is associated with epileptic activity in rats (p < .05). In a second experiment, WAG/Rij rats were divided into 3 groups: untreated (H2O), temporary early treatment (ESX 4 month), and continuous early treatment (ESX continuous), and SWD activity was measured by electroencephalogram (EEG) at various timepoints. This second experiment revealed that animals in the ESX 4 month group spent less percent time in SWD (0.242 ± .068 SEM) than animals in the H2O group (0.769 ± .060 SEM, p < .001), although they spent slightly more percent time in SWD than animals in the ESX continuous group (0.020 ± .065 SEM, p = .003). This effect was predominantly due to seizure number, and average seizure duration did not vary among the three groups. Additionally, power spectrum analysis revealed a significant correlation when the difference between power spectra for H2O and ESX 4 month rats was compared to the power spectrum of a seizure (Pearson correlation equals 0.955, 2-tailed significance < .000000001), suggesting quantitatively that seizures were reduced by temporary early treatment. This suggests that early prevention of SWD may reduce the burden of seizures later in life, and that possibilities for prevention of genetic absence epilepsy should be further investigated.

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This is an Open Access Thesis.

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