Abstracts

Glucose uptake into the brain is greater during epileptic seizures than during most other brain activities suggesting a key role for glucose in the initiation and spread of seizure activity. Under conditions of fasting or caloric restriction (CR), however, brain cells can also derive energy from ketone bodies. Consequently, high fat, low protein, low carbohydrate ketogenic diets (KD) were developed to mimic the physiological effects of fasting for seizure control. While the mechanisms by which fasting and the KD inhibit seizures remain speculative, a transition from glucose to ketone bodies for brain energy is likely involved. This transition in brain energy metabolism likely produces multiple changes in gene and protein expression levels that ultimately lead to reduced neuronal membrane excitability and seizure protection. We previously showed that CR inhibits seizure susceptibility, and that the KD inhibits epileptogenesis in the epileptic EL mouse, a model of human multifactorial idiopathic epilepsy. In this study, we compared the antiepileptic and anticonvulsant efficacy of the KD with that of CR in adult EL mice, and studied the expression levels of various genes potentially involved in the metabolic control of seizures by these diets. Adult EL mice that experienced at least 15 recurrent complex partial seizures were fed either a standard (chow) diet unrestricted (SD-UR) or restricted (SD-R), and either a KD unrestricted (KD-UR) or restricted (KD-R). A new experimental design was used where each mouse in the diet-restricted groups served as its own control to achieve a 20% body weight reduction. Seizure susceptibility, body weights, and the levels of plasma glucose and [beta]-hydroxybutyrate were measured once a week over a nine-week treatment period in each diet group. Gene expression levels were analyzed by RT-PCR under the four dietary conditions. Seizure susceptibility remained high in both UR-fed groups throughout the study, but was significantly reduced after three weeks in both R-fed groups. Body weights and plasma glucose levels remained high over the nine-week testing period in the SD-UR and the KD-UR groups, but were significantly reduced in the SD-R and KD-R groups. Plasma [beta]-hydroxybutyrate levels were significantly increased in the SD-R and KD-R groups compared to their respective UR groups. Preliminary RT-PCR data have been obtained for the expression profiles of various genes (MCT1, GLUT1, NPY, and GAD). Additional RT-PCR data are needed to test statistical variance. A reduction in plasma glucose levels coupled with an increase in plasma ketone levels is predicted to manage EL epileptic seizures through multiple integrated changes of inhibitory and excitatory neural systems. (Supported by the Epilepsy Foundation, the NIH grant (HD39722), and the Boston College Research Expense Fund.)