Path Analysis Shows That Increasing Ketogenic Ratio, but Not β-Hydroxybutyrate, Elevates Seizure Threshold in the Rat

Bough, Kristopher J.; Chen, Ru San; Eagles, Douglas A.

doi:10.1159/000017390

Cited by 54 publications

(38 citation statements)

References 27 publications

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“…The animals tolerated the diet well, with none of the animals losing weight after starting the KD or regular rat chow. As previously described (10,37,38), animals that consumed the KD gained substantially less weight than the controls in both the SE and NoSE groups (weights at P57: SE-KD 123.5 Ϯ 9.06 g; SECont 205.6 Ϯ 8.60 g, NoSE-KD 117.1 Ϯ 8.10 g, NoSE-Cont 251.1 Ϯ 9.52 g; p Ͻ 0.001). Both the SE and NoSE groups were significantly lighter than the corresponding groups that received regular rat chow (p Ͻ 0.001).…”

Section: Resultssupporting

confidence: 61%

Detrimental Effects of the Ketogenic Diet on Cognitive Function in Rats

et al. 2004

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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...

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Section: Resultssupporting

confidence: 61%

Detrimental Effects of the Ketogenic Diet on Cognitive Function in Rats

et al. 2004

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“…However, the link between ketone bodies and the anticonvulsant efficacy of the ketogenic diet is not as clear. Studies of the effects of the ketogenic diet on pentylenetetrazol threshold in rats have failed to show an association between plasma β-hydroxybutyrate levels and seizure threshold [16]. Moreover, exogenously administered β-hydroxybutyrate is not anticonvulsant in animal models such as the Frings audiogenic seizure-susceptible mouse [17].…”

Section: Do Ketone Bodies Mediate the Effects Of The Ketogenic Diet?mentioning

confidence: 99%

The Neuropharmacology of the Ketogenic Diet

Hartman

Gąsior

Vining

et al. 2007

Pediatric Neurology

277

169

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The ketogenic diet is a valuable therapeutic approach for epilepsy, one in which most clinical experience has been with children. Although the mechanism by which the diet protects against seizures is unknown, there is evidence that it causes effects on intermediary metabolism that influence the dynamics of the major inhibitory and excitatory neurotransmitter systems in brain. The pattern of protection of the ketogenic diet in animal models of seizures is distinct from that of other anticonvulsants, suggesting that it has a unique mechanism of action. During consumption of the ketogenic diet, marked alterations in brain energy metabolism occur, with ketone bodies partly replacing glucose as fuel. Whether these metabolic changes contribute to acute seizure protection is unclear; however, the ketone body acetone has anticonvulsant activity and could play a role in the seizure protection afforded by the diet. In addition to acute seizure protection, the ketogenic diet provides protection against the development of spontaneous recurrent seizures in models of chronic epilepsy, and it has neuroprotective properties in diverse models of neurodegenerative disease.

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“…For example, increasing the ketogenic ratio, but not the levels of β-hydroxybutyrate, may be directly involved in the anticonvulsant mechanism of the KD [68]. Although elevated levels of β-hydroxybutyrate were observed in children on the KD (as compared with prediet), levels of β-hydroxybutyrate did not correlate with their seizures.…”

Section: Discussionmentioning

confidence: 93%

Ketogenic diet decreases circulating concentrations of neuroactive steroids of female rats

Rhodes

Talluri

Harney

et al. 2005

Epilepsy & Behavior

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Ketogenic diet (KD) is used to manage intractable epilepsy; however, the mechanisms underlying its therapeutic effects are not known. Steroid hormones, such as progesterone and testosterone, are derived from cholesterol, and are readily 5α-reduced to dihy-droprogesterone and dihydrotestosterone, which are subsequently converted to 5α-pregnan-3α-ol-20-one (3α,5α-THP) and 3α-androstanediol, neuroactive steroids that can influence seizures. The present study examined the effects of the KD on circulating concentrations of these neuroactive steroids, and their precursors, in intact female rats. Thirty-six, 22-day-old female Sprague-Dawley rats (weaned at 21 days) were fasted for 8 hours prior to placement on one of three dietary regimens for 6 weeks: ad libitum chow, calorie-restricted chow, or KD. After 6 weeks of the diet, when six rats in each dietary condition were in diestrus and six were in behavioral estrus, all rats were administered pentylenetetrazole (PTZ, 70 mg/kg, IP). The latency and incidence of seizures were recorded by an observer who was uninformed of the estrous cycle and dietary treatment conditions of the rats. Immediately after each test, trunk blood was obtained for later measurement of pregnane (progesterone, dihydroprogesterone, 3α,5α-THP) and androstane (testosterone, dihydrotestosterone, 3α-androstanediol) neuroactive steroid concentrations in plasma by radioimmunoassay. KD tended to lengthen the latency to, and significantly reduced the number of, PTZ-induced barrel roll seizures. KD also significantly reduced plasma levels of the pregnane (dihydroprogesterone, 3α,5α-THP) and androstane (dihydrotestosterone, 3α-androstanediol) 5α-reduced metabolites. These data suggest that levels of pregnane and androstane neuroactive steroids, or their precursors, may underlie some of the antiseizure effects of KD.

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Path Analysis Shows That Increasing Ketogenic Ratio, but Not β-Hydroxybutyrate, Elevates Seizure Threshold in the Rat

Cited by 54 publications

References 27 publications

Detrimental Effects of the Ketogenic Diet on Cognitive Function in Rats

Detrimental Effects of the Ketogenic Diet on Cognitive Function in Rats

The Neuropharmacology of the Ketogenic Diet

Ketogenic diet decreases circulating concentrations of neuroactive steroids of female rats

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