A ketogenic diet delays weight loss and does not impair working memory or motor function in the R6/2 1J mouse model of Huntington's disease

Abstract

Ketogenic diets are high in fat and low in carbohydrates, and have long been used as an anticonvulsant therapy for drug-intractable and pediatric epilepsy. Additionally, ketogenic diets have been shown to provide neuroprotective effects against acute and chronic brain injury, including beneficial effects in various rodent models of neurodegeneration. Huntington’s disease is a progressive neurodegenerative disease characterized by neurological, behavioral and metabolic dysfunction, and ketogenic diets have been shown to increase energy molecules and mitochondrial function. We tested the effects of a ketogenic diet in a transgenic mouse model of Huntington’s disease (R6/2 1J), with a focus on life-long behavioral and physiological effects. Matched male and female wild-type and transgenic mice were maintained on a control diet or were switched to a ketogenic diet fed ad libitum starting at six weeks of age. We found no negative effects of the ketogenic diet on any behavioral parameter tested (locomotor activity and coordination, working memory) and no significant change in lifespan. Progressive weight loss is a hallmark feature of Huntington’s disease, yet we found that the ketogenic diet - which generally causes weight loss in normal animals - delayed the reduction in body weight of the transgenic mice. These results suggest that metabolic therapies could offer important benefits for Huntington’s disease without negative behavioral or physiological consequences.

Partial Amelioration of Peripheral and Central Symptoms of Huntington’s Disease via Modulation of Lipid Metabolism

“…Confirming a previous study [40], we observed delayed weight loss in HD mice fed with the KD (Fig. 4A, left graph ).…”

“…Essential fatty acids (phospholipid components of cell membranes) given from conception prevented weight loss and behavioral deficits in R6/1 mice [68] and one study specifically using the KD in R6/2 mice reported some beneficial effects, including delayed weight loss, and no obvious deleterious effects [40]. Considering that in HD energy metabolism is significantly altered due to reduced gluconeogenesis in spite of increased demand, we expected that these alterations could be rescued in animals treated with a KD.…”

Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse

“…In normally social control strains, we found KD feeding produced no significant change in sociability or in STFP; in control strains with normal grooming levels, KD similarly produced no change [39]. We also found a lack of effect of KD feeding on working memory in control mouse strains [48] and a lack of effect on baseline hippocampal electrophysiology in vitro in control strains (but an impact on chemically-induced epileptiform activity; [56]). We found normal in vivo baseline hippocampal field potential activity (but a lessening of induced seizures or tetanus-induced potentiation; [53,54,57].…”

“…This formula is typically used in research, but is a much higher ratio than prescribed clinically (typically between 1:1 and 4:1). Additionally, all previous studies were in male animals, and ketogenic diet effects on females are underexplored [46,48]. …”

Ketogenic Diets and Pain

“…We found that this increased latency to thermal pain was present in juvenile and adult rats, 22 and in other studies determined that the ketogenic diet does not impact motor function. 23, 24 Therefore, motor deficits did not underlie this increased behavioral latency.…”