Baldwin, Tomas; (2021) Identifying the downstream metabolic effects of exposure to decanoic acid. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Approximately 30% of patients suffering with epilepsy are resistant to traditional anti- epileptic drugs. These patients can effectively be treated using a medium chain triglyceride (MCT) ketogenic diet. However, the mechanisms of seizure reduction remain unclear. The primary aim of this thesis was to assess biochemical changes occurring in the brains of Scn1aR1407X/+mice, a model of Dravet syndrome, to further our understanding of the mechanisms of seizure reduction brought about during MCT supplementation. Our findings suggest that reduced seizure frequency is associated with increased levels of free C10 in the brain. Additionally, mice supplemented C10 and C8 in an 80/20 ratio were found to have significant increases in citrate synthase activity and relative mtDNA content, indicative of mitochondrial proliferation. Enzyme activities of the mitochondrial electron transport chain were also up-regulated in 80/20 treatment group, suggesting energy metabolism may be improved. Mice in all treatment groups were found to have improved antioxidant capacity as indicated by observed increases in several important antioxidant molecules. The findings reported here not only suggest that seizure reduction can be achieved through dietary supplementation with MCTs instead of a full diet, but this seizure reduction is associated with increased brain C10 levels, improved mitochondrial content and antioxidant status. The effects of MCFA exposure on peroxisomal content and function was evaluated using the neuroblastoma cell line SH-SY5Y. C10, but not C8, led to significant increases in markers of peroxisomal content, indicative of peroxisomal biogenesis. Furthermore, there was evidence of increased peroxisomal long chain fatty acid oxidation in C10 treated cells, suggesting that peroxisomal function was also improved. Untargeted proteomic screening indicated that alterations in VEGF signalling, calcium homeostasis and inflammatory signalling may also play a role in seizure reduction observed following MCT supplementation in Scn1aR1407X/+mice.

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