Protective effects of medium chain triglyceride diet in a mouse model of Dravet syndrome

Abstract

ObjectiveDravet syndrome (DS) is a severe developmental and epileptic encephalopathy with early childhood onset. Patients with DS do not respond well to antiepileptic drugs and have only a few treatment options available. Here, we evaluated the effect of medium chain triglyceride (MCT) diet therapy in a mouse model of DS.MethodsScn1aR1407X/+ DS mice were given diets supplemented with MCTs with varying ratios of decanoic (C10) and octanoic (C8) acid or a control diet for 4 weeks. Video monitoring was performed to evaluate spontaneous convulsive seizure frequency. Susceptibility to hyperthermia‐induced seizures was also examined. Medium chain fatty acids, and mitochondrial and antioxidant markers were assessed in brain homogenate.ResultsDietary intervention with MCTs significantly prolonged survival and reduced convulsive seizure frequency during the critical period of highest seizure occurrence in the Scn1aR1407X/+ DS mice. Moreover, MCT diet therapy showed protective effects against hyperthermia‐induced seizures. We demonstrated that coadministration of C10/C8 was effective at reducing both seizures and mortality, whereas C10 alone only reduced mortality, suggesting that the ratio of C10 to C8 in the MCT is an important factor for efficacy. When C10 and C8 are supplemented at an 80:20 ratio in the diet, C10 accumulates in the brain in high enough concentrations to enhance brain energy metabolism by both stimulating mitochondrial enrichment and increasing its antioxidant status.SignificanceThe results from this study indicate that MCT diet therapy may provide therapeutic benefits in DS. Future clinical studies would elucidate whether these positive effects are mirrored in human patients.

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

“…There has also been a remarkable progress in screening for new treatments for Dravet syndrome, using both rodents (233,384,(549)(550)(551)(552)(553)(554)(555)(556)(557)(558) as well as high throughput studies in zebrafish (391,(559)(560)(561)(562)(563)(564). A noteworthy development has been the recent approval by the Food and Drug Administration of fenfluramine, a reuptake inhibitor of 5-OH-tryptamine, for the treatment of Dravet syndrome, based on evidence provided by both preclinical (560, 561) and clinical trials (230,(565)(566)(567)(568)(569).…”

Potential benefits of medium chain fatty acids in aging and neurodegenerative disease

“…In pre-clinical trials, the classic ketogenic diet has been proven beneficial in the treatment of multiple diseases and disorders. For example, ketone-producing diet can prolong life and reduce seizures in mouse models of Dravet syndrome, an early onset childhood developmental disorder with severe epileptic encephalopathy ( Jancovski et al, 2021 ). A reduction in anxiety is seen in rats on the MCT diet, along with an increase in social competitiveness ( Hollis et al, 2018 ).…”

Alternative Substrates in the Critically Ill Subject (ASICS): Safety, Feasibility, Tolerability and Metabolic Profiling of a Novel Ketogenic Feed

“…Plasma medium chain fatty acids, lactate, and beta-hydroxybutyrate, whole blood acetoacetate pyruvate, and urinary beta-hydroxybutyrate were analysed by gas chromatography/mass spectrometry 34 .…”