Bound Volume Number

Volume II

Document Type

Honors Capstone Project

Date of Submission

Spring 5-2016

Capstone Advisor

James Hewett

Capstone Major

Biomedical and Chemical Engineering

Capstone College

Arts and Science

Audio/Visual Component

no

Keywords

Epilepsy, spontaneous seizure activity, Catamenial epilepsy

Capstone Prize Winner

no

Won Capstone Funding

no

Honors Categories

Sciences and Engineering

Subject Categories

Biochemistry

Abstract

Epilepsy is a neurological disease that is characterized by spontaneous seizure activity. Seizures are excitatory events that result from the abnormal excessive and hypersynchronous firing of populations of neurons in the brain. Catamenial epilepsy is a condition in which seizure threshold fluctuates during the female menstrual cycle. It is commonly hypothesized that this fluctuation is due to the changes in estradiol:progesterone ratio that occur over the course of the menstrual cycle (Herzog, 2008). It has been shown in many studies that estradiol has proconvulsant properties whereas progesterone possesses anticonvulsant properties. Considering the pattern of hormonal variation and the effects of sex hormones on seizure threshold, a female would be most susceptible to seizure activity when estradiol levels are high and/or immediately following progesterone withdrawal. Cyclooxygenase-2 (COX-2) is an enzyme that facilitates the first committed step in the metabolism of arachidonic acid to biologically active prostaglandins. It has been shown to serve as an endogenous suppressor of seizures. Its expression is constitutively expressed in subsets of excitatory glutamateric neuronal populations and it is intensely induced under conditions of strong excitation, such as occurs during convulsive seizures (Hewett, 2006). Inhibitors of COX-2 enhance the sensitivity to and severity of acute seizures. However, its role in the fluctuation of seizure threshold in catamenial epilepsy remained to be explored. Given that both COX-2 and progesterone possess anticonvulsive properties, the goal of this study was to examine the possible correlative relationship between these two neuromodulators. Considering the influence of female sex hormones on seizures, it was posited that both seizure sensitivity and brain COX-2 expression levels will vary over the course of the estrous cycle and that the latter will be inversely related to the former. Studies were performed with female mice, which were treated with pentylenetetrazol (PTZ), a GABA-A receptor inhibitor, to model acute seizures. Results showed that COX-2 expression does indeed fluctuate consistently over the timeframe of the estrous cycle and that this may correlate with hormonal changes in the brain. An additional related study was performed to examine the possibility that sensitivity to PTZ differed between female and male mice. It was observed that females were more resistant to PTZ-induced convulsion than males. This project was a new direct of the research in the Hewett laboratory. The results established an animal model of catamenial epilepsy in mice that will provide the basis for future studies to examine the role of neuromodulators in seizure sensitivity.

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