Oxidative Stress and the Ketogenic Diet

This application is for a bi-institutional collaborative Exploratory/Developmental Award in Epilepsy Research for Junior Investigators. The PI is an Assistant Professor at the University of Kentucky. and although published extensively in the field of mitochondrial bioenergetics and mitochondria-mediated cellular injury and death. he is relatively new to the field of epilepsy research. While conduding a post-doctoral research fellowship last year, the PI initiated an innovative collaboration with an established epilepsy researcher at the University of California at Irvine. The co-investigator is an expert on mechanisms underlying the anticonvulsant actions of the ketogenic diet (KD), an effective non pharmacological treatment for medically refractory epilepsy. The KD is a high-fat, low-carbohydrate and low-protein diet designed to reproduce the early biochemical changes seen upon fasting. Despite decades of successful clinical experience with the KO, the mechanisms underlying its anticonvulsant actions remain poorly understood. It is well known that fasting increases peripheral mitochondrial uncoupling protein (UCP) activity. However, there are no data addressing the effects of a KD on brain mitochondrial uncoupling. In preliminary studies, we have found that a KD enhances fatty acid-induced mitochondrial uncoupling and decreases reactive oxygen species (ROS) production in normal mouse cortex. The fundamental goal of the proposed studies is to determine whether a KD decreases mitochondrial oxidative damage in the hippocampus of developing epileptic mice (Kcna1-null). Specifically, we hypothesize that a KD increases UCP-mediated mitochondrial uncoupling and reduces subsequent ROS formation in epileptic hippocampus to a greater degree than in wild-type mice. Additionally, we will determine whether ketone bodies alone can also induce such changes, either acutely and/or chronically. Specifically, we will study acutely isolated mitochondria from the hippocampus of KD-fed Kcna1-null epileptic mice and hippocampal slice cultures (prepared from these mice) incubated chronically with ketone bodies. The results of these studies will shed light on whether a KD reduces oxidative stress in the epileptic hippocampus. The clinical importance of such findings is that this therapy may ameliorate the epileptic condition itself, and not merely halt spontaneous recurrent seizure activity .