Detrimental Effects of the Ketogenic Diet on Cognitive Function in Rats

Abstract

The ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that is widely used to treat epilepsy in children. Although the KD has been shown to be efficacious in the treatment of childhood epilepsy, the long-term effects of the KD on brain development are not clear. The objective of this study was to examine the long-term effects of the KD on visual-spatial memory, activity level, and emotionality in immature rats after status epilepticus (SE). Weanling rats were subjected to lithium/ pilocarpine-induced SE or saline injections and were then randomized to either the KD or regular rat diet, both fed ad libitum. One month later, rats were evaluated for visual-spatial memory in the water maze, activity level in the open field test, and emotionality with the handling test. Spontaneous recurrent seizures were measured using videotaping, and seizure susceptibility was tested with flurothyl inhalation. Brains were weighed and examined for mossy fiber sprouting and cell loss. Although rats treated with the KD were active and seemed healthy, their weight gain was substantially lower than that in rats that received regular rat diet. The KD reduced the number of spontaneous seizures but had no discernible effect on flurothyl seizure susceptibility. KDfed rats, with or without SE, had significantly impaired visualspatial learning and memory compared with rats that were fed regular diet. The KD had minimal effects on activity level and emotionality. Rats that were treated with the KD had significantly impaired brain growth. No differences in pathology scores between the KD and regular diet groups were seen after SE. Despite reducing the number of spontaneous seizures after SE, the KD resulted in severe impairment in visual-spatial memory and decreased brain growth, with no effect on mossy fiber sprouting. This study raises concerns about the long-term effects of the KD on brain development. The ketogenic diet (KD) is a high-fat, low-carbohydrate, and low-protein diet that is now widely used to treat epilepsy (1-4). Although the diet has not undergone the rigorous evaluation process required for marketing of antiepileptic drugs, there is now a considerable body of evidence indicating that the KD is efficacious in the treatment of epilepsy (1,2,5,6).Despite the use of the KD over several decades, the long-term effects of the KD on cognition are not yet known. Anecdotal reports suggest improvements in alertness, cognitive function, and behavior (2), although impairments in patients have also been reported (7). In a prospective study on the effects of the KD, Pulsifer et al. (8) found that developmental quotients in children on the diet improved after 1 y. One of the difficulties in evaluating cognitive effects of the KD in children is that the diet is rarely continued in children who do not respond with a reduction in seizure frequency (5, 9). The improvement in cognitive function therefore may represent the effects of reduced seizures, a positive cognitive effect of the diet, or a combination of these facto...

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype

“…Clinically, the KD is associated with significantly attenuated growth compared to humans consuming a non-KD (Vining et al, 2002;Liu et al, 2003;Papandreou et al, 2006). This has also been shown in rats fed a KD (Zhao et al, 2004;Nylen et al, 2005;Nylen et al, 2006). This held true in the KD fed mutants as they showed significant stunting of growth when compared to CD fed wildtype mice.…”

“…We did not measure weight gain in KD fed Aldh5a1 +/+ mice. There are several studies, both clinical and experimental, that report KD fed subjects being lighter than normal diet fed subjects (Rho et al, 1999;Bough & Eagles, 2001;Vining et al, 2002;Zhao et al, 2004;Nylen et al, 2005). Despite having significantly stunted growth, rodents fed a KD do not experience anywhere near the stunting seen in SSADH mutants fed either a KD or a CD.…”

Synaptically released zinc gates long-term potentiation in fear conditioning pathways

“…RNA in situ hybridization was performed as described previously (31). Timm staining was performed by using a modification of a previously published protocol (30,32). Briefly, a 1-month-old rat (125 g body weight) was anesthetized by 3.5 ml of 1.25% Avertin solution i.p.…”

Cerebral Metabolic Adaptation and Ketone Metabolism after Brain Injury

“…In addition to this clinical finding, an experimental study has also reported cognitive and behavioral adverse consequences. Zhao et al (2004) tested weanling rats maintained on a ketogenic diet for 30 days in the Morris water maze, open field test, brain weights, time to seizure onset, and hippocampal cell loss. No ketogenic effects were found in the activity, emotionality, or pathology, but there was significant reduction in seizure activity.…”