Professor Simon Heales, University College London
From Bench to Patients; Decanoic/Octanoic Acid & Brain Energy
Ketogenic diets, as a treatment for patients with epilepsy have been known for a considerable period. Whilst effective, in particular for patients with pharmacoreistant epilepsy, compliance is an issue. Furthermore, despite many years of use, the mechanism whereby the diet exerts its beneficial effects is not known. With this in mind, we set about to characterise biochemical changes in response to exposure to octanoic (C8) and/or decanoic (C10) acid, key components of the medium chain triglyceride form of the diet. As compromised energy metabolism, including loss of mitochondrial function, is reported to be associated with seizures this became the focus of our study. Using a neuronal cell line (SHSY5Y cells), C10 (250µM) but not C8 (250µM) was found to increase activities of citrate synthase and complex I, mitochondrial membrane potential and mitochondrial DNA content. Activation of PPARɤ, via C10, was proposed to be the mechanism for these changes. In addition to these findings, C10, in contrast to C8, was found to be dependent upon the carnitine shuttle for oxidation. As the carnitine shuttle may be relatively poorly expressed in the brain, this could lead to accumulation of C10. With regards to this, co incubation of C8 (20%) with C10 (80%) further slowed the oxidation of C10. This sparing effect, by C8, upon C10 may permit its gradual accumulation therefore also enabling it to act as fuel reserve. Extending our studies to the Dravet mouse model, our findings, in vitro, were replicated in the brain of these animals. Furthermore, the 80:20 (C10:C8) ratio was found to provide superior seizure control and greater brain C10 accumulation compared to conventional fatty acid ratios. Consideration of these findings permitted a feasibility trial to proceed for patients with drug resistant epilepsy. This trial, which allowed a relatively liberal diet, used a formulation (K-Vita) consisting of 80% C10 and 20% C8 and had a paediatric and adult arm. Data form the study revealed an overall 50% reduction in seizures. In contrast to traditional diets, there was no evidence of ketosis. However, both plasma C10 and C8 were elevated. K-Vita has now received approval as a food for special medical purposes in adults and children.