KETOGENIC DIET THERAPY FOR EPILEPSY AND BRAIN CANCER

The high fat, low carbohydrate, low protein ketogenic diet (KD) was developed as an alternative to fasting for the management of epileptic seizures. Most epilepsies, regardless of etiology, are disorders of brain energy metabolism. While the mechanisms by which fasting and the KD manage epileptic seizures remain speculative, adjustments in brain energy metabolism are likely involved. In addition to epilepsy, brain cancer is a metabolic disorder involving the dysregulation of glycolysis and respiration. Most brain tumors are dependent on glucose for energy due to mitochondrial defects. Functional mitochondria are required for the energetic oxidation of ketone bodies. Our recent findings in animal models indicate that the bioenergetic transition from glucose to ketone bodies manages both epilepsy and brain cancer through compensatory genetic and biochemical pathways that regulate the bioenergetic potential of cells and ultimately the disease phenotype. We evaluated the therapeutic efficacy of KetoCal, a new specially formulated ketogenic diet for children, on seizure susceptibility in EL mice with idiopathic epilepsy, and on the growth and vascularity of malignant mouse brain tumors. A reduction of plasma glucose with a corresponding elevation of plasma ketone bodies was associated with reduced seizure susceptibility in EL mice, and with reduced growth and angiogenesis in the mouse brain tumors. The administration of KetoCal in restricted amounts (caloric restriction) is essential for therapeutic efficacy. We propose that the bioenergetic transition from glucose to ketone bodies manages epilepsy by restoring the balance of inhibitory and excitatory neural systems. On the other hand, this bioenergetic transition targets brain tumors through integrated anti-inflammatory, anti-angiogenic, and pro-apoptotic mechanisms. The KD offers an alternative therapeutic strategy for a broad range of neurological disorders. Supported by NIH grants HD39722 and CA102135.