581 S. Masino and D. Boison (eds.), Adenosine: A Key Link between Metabolism and Brain Activity, DOI 10.1007/978-1-4614-3903-5_27, © Springer Science+Business Media New York 2013 Abstract The ketogenic diet (KD) debuted in the 1920s as a metabolic treatment for epilepsy, based on the historical observation that fasting could prevent seizures. Similar to fasting, the high-fat, low-carbohydrate KD restricts glucose and favors oxidation of fatty acids, which in turn generates ketones for energy. Despite nearly a century of clinical use, proof of efficacy was only recently established, and little is known about how the KD works. The lure of a continually growing armamen- tarium of pharmacological options and the inherent challenges in implementing a dietary treatment versus a drug have combined to relegate the KD to a therapy of last resort. Indeed, better knowledge of how the KD exerts broad-spectrum clinical activity would be required to develop enhanced metabolism-based treatments, and perhaps even a “diet in a pill.” Recent evidence strongly implicates adenosine as a mediator of KD action, as it is well known that adenosine is a fundamental link between metabolism and neuronal membrane excitability. Through a greater mech- anistic understanding of how the KD―and adenosine in particular―works to dampen aberrant excitation in the brain, novel insights and molecular targets are bound to emerge. However, given the complexity of metabolic pathways in both normal and disease states, it will be important to determine specific cause-and-effect relationships. At present, given growing interest in metabolic dysfunction as a major pathophysiological substrate for a multiplicity of disease states, as well as urgent J.M. Rho Departments of Pediatrics and Clinical Neurosciences, Alberta Children’s Hospital, University of Calgary, Calgary, AB, Canada B. Zupec-Kania Ketogenic Seminars, The Charlie Foundation, Santa Monica, CA, USA S.A. Masino (*) Neuroscience Program and Psychology Department, Trinity College, Life Sciences Center 210 300 Summit Street, Hartford, CT 06016, USA e-mail: Susan.Masino@trincoll.edu Chapter 27 Ketogenic Diet and Epilepsy: The Role of Adenosine Jong M. Rho, Beth Zupec-Kania, and Susan A. Masino