Grant: Project Grant

Epilepsy is a common neurological problem affecting approximately 1% of the general population. While current medical treatments are effective in two-thirds of patients, there are associated short-term and long-term side-effects of drugs that pose potentially serious health risks. Moreover, the remaining third of patients with epilepsy continue to have seizures that impair quality of life and increase the risk of brain damage and even sudden unexpected death. Hence, there is an urgent need to identify new treatments that can both increase effectiveness, but also minimize undesired side-effects. A remarkable non-drug treatment for difficult-to-control epilepsy is the ketogenic diet, a high-fat and low-carbohydrate regimen that often works when medications fail. While we do not yet fully understand how this diet works, there is increasing evidence that ketone bodies - chemicals produced by the liver as a result of this diet - may be critical players. Specifically, we hypothesize that ketone bodies produce beneficial changes within the energy factories of cells (called "mitochondria") that prevent both seizures and cell death. Our preliminary studies indicate that ketone bodies increase the activity of a specific enzyme family known Sirt3 (i.e., sirtuin 3) and that these enzymes alter the chemical structure of an important protein within the mitochondria called cyclophilin D (or CypD) which helps determine whether cells live or die. The major goal of the proposed studies is to identify the precise mechanism of how ketone bodies produce anti-seizure effects, and in so doing highlight novel targets within mitochondria that can be exploited for the development of better treatments for medically intractable epilepsy. Specific experiments will be conducted to show that the hypothesized mechanism is relevant to multiple types of epilepsy in laboratory models, a necessary step before new treatments emerging from this research can be tested in humans.