Ketogenic and anaplerotic dietary modifications ameliorate seizure activity in Drosophila models of mitochondrial encephalomyopathy and glycolytic enzymopathy

Abstract

Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern antiepileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, with a wide array of downstream effects at the genetic, protein, and metabolite level that may mediate seizure protection. We have recently shown that a Drosophila model of human ME (ATP6 1

Non-pharmacological Interventions for Intractable Epilepsy

“…These ketone bodies can cross the blood–brain barrier and are used as a source of energy in the absence of glucose ( Gu et al, 2009 ). A recent study has reported that supplementation with triheptanoin simulates the effects of ketogenic-diet even in the presence of standard carbohydrates level ( Fogle et al, 2019 , Wehbe and Tucci, 2019 ). Replenishing of TCA-cycle intermediates augments the synthesis of ATP which essentially causes the stabilization of membrane potential and contributes to the anticonvulsant mechanism of the triheptanoin and substrates of the TCA-cycle as shown in Fig.…”

Characterization of Seizure Induction Methods inDrosophila

“…This might be explained by accumulation of genetic modifiers over time. Alterations in food composition are also known to affect seizure phenotype in flies and potential differences in fly food could also impact secondary phenotypes observed ( Stone et al, 2013 ; Fogle et al, 2019 ; Kasuya et al, 2019 ). On the other hand, the overall trend we observed matches previously reported data where seizure mutants are, overall, less active than controls ( Radlicz et al, 2019 ).…”

Therapeutic potential of triheptanoin in metabolic and neurodegenerative diseases

“…Very recent studies in drosophila models of mitochondrial encephalopathy and glycolytic enzymopathy have shown that supplementation of triheptanoin mimics the success of the ketogenic diet even in the presence of standard carbohydrate levels due to its anaplerotic effect . Moreover, triheptanoin does not appear to alter glucose metabolism in the healthy brain .…”

“…AR, anaplerotic reaction; ATP, adenosine triphosphate; BKP, β-ketopentanoate; BHP, β-hydroxypentanoate; CII, complex II of the electron transport chain; NADH/FADH 2 , nicotinamide adenine dinucleotide/flavin adenine dinucleotide; TCA, citric acid cycle effect. 10 Moreover, triheptanoin does not appear to alter glucose metabolism in the healthy brain. 11 Of note, the mechanism of action of triheptanoin depends on the modality of administration.…”