Glucose reduces the anticonvulsant effects of the ketogenic diet in EL mice

Mantis, John G.; Meidenbauer, Joshua; Zimick, Nicholas C.; Centeno, Nicole A.; Seyfried, Thomas N.

doi:10.1016/j.eplepsyres.2014.05.010

Cited by 15 publications

(14 citation statements)

References 71 publications

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“…This is consistent with our previous work demonstrating that acute supplementation of glucose does not lead to an increase in circulating glucose levels [18]. This is also consistent with other work demonstrating that low circulating blood glucose leads to rapid blood glucose clearance in humans after a bolus of glucose [28], and ketone bodies are rapidly cleared from plasma in rats under calorie-restricted conditions [29].…”

Section: Discussionsupporting

confidence: 93%

“…This is consistent with our previous results demonstrating that chronic bOHB supplementation in the drinking water of calorie-restricted EL mice did not result in additional anticonvulsant activity compared to calorie-restricted controls [18]. We cannot completely rule out that supplementing higher levels of ketone bodies may be anticonvulsant in the EL mouse, however a solution of 50 mM bOHB was the highest concentration EL mice could tolerate before restricting fluid intake.…”

Section: Discussionsupporting

confidence: 91%

“…This is also consistent with other work demonstrating that low circulating blood glucose leads to rapid blood glucose clearance in humans after a bolus of glucose [28], and ketone bodies are rapidly cleared from plasma in rats under calorie-restricted conditions [29]. Rapid blood glucose clearance is associated with increased cerebral glucose utilization and seizures [18, 30]. Rapid bOHB clearance does not appear to be associated with seizure incidence.…”

Section: Discussionsupporting

confidence: 91%

“…We confirmed from previous work that long-term calorie restriction significantly reduces seizure susceptibility in EL mice [5], and that acute addition of glucose abolishes the seizure-protective effects of calorie restriction [18]. We found that reduced glucose utilization is necessary for acutely managing seizures with dietary therapy in EL mice, whereas acute supplementation of bOHB does not have a seizure-protective role for EL mice, in the presence of increased glucose availability.…”

Section: Discussionsupporting

confidence: 89%

“…Seizures in EL mice can be managed through AED and dietary therapy, which makes the EL mouse an ideal model to study the mechanisms through how seizure protection is conferred [5, 6, 16, 17]. We previously found that EL mice given a calorie-restricted ketogenic diet had reduced seizure susceptibility, but that subsequent acute supplementation of glucose resulted in significantly increased seizure susceptibility [18]. We confirmed these results using a calorie-restricted standard mouse chow diet, and additionally analyzed the acute effect of lowering glucose utilization or increasing β-hydroxybutyrate availability on seizure susceptibility.…”

Section: Introductionmentioning

confidence: 99%

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Reduced glucose utilization underlies seizure protection with dietary therapy in epileptic EL mice

Meidenbauer

Roberts

2014

Epilepsy & Behavior

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Dietary therapy has been used to treat many individuals with epilepsy that are refractory to anti-epileptic drugs. The mechanisms for how dietary therapy confers seizure protection are currently not well understood. We evaluated the acute effects of glucose and β-hydroxybutyrate (the major circulating ketone body) in conferring seizure protection to the EL mouse, a model of multifactorial idiopathic generalized epilepsy. EL mice were fed either a standard diet unrestricted or a calorie-restricted standard diet to achieve a body weight reduction of 20–23%. D-glucose, 2-deoxy-D-glucose, and β-hydroxybutyrate were supplemented in the drinking water of calorie-restricted mice for 2.5 hours prior to seizure testing to simulate the effect of increased glucose availability, decreased glucose utilization, and increased ketone availability, respectively. Seizure susceptibility, body weight, plasma glucose and β-hydroxybutyrate were measured over a nine-week treatment period. Additionally, excitatory and inhibitory amino acids were measured in the brains of mice using 1H NMR. Glutamate decarboxylase activity was also measured to evaluate the connection between dietary therapy and brain metabolism. We found that lowering of glucose utilization is necessary to confer seizure protection with long-term (>4 weeks) calorie restriction, whereas increased ketone availability did not affect seizure susceptibility. In the absence of long-term calorie restriction, however, reduced glucose utilization and increased ketone availability did not affect seizure susceptibility. Brain excitatory and inhibitory amino acid content did not change with treatment, and glutamate decarboxylase activity was not associated with seizure susceptibility. We demonstrate that reduced glucose utilization is necessary to confer seizure protection under long-term calorie restriction in EL mice, while acute ketone supplementation did not confer seizure protection. Further studies are needed to uncover the mechanisms by which glucose utilization influences seizure susceptibility.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%