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Published on: August 15, 2017
Different ketogenesis strategies lead to disparate seizure outcomes
Alison Dolce1, Polan Santos2, Weiran Chen2
1Department of Neurology, Johns Hopkins School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA; Departments of Pediatrics, Neurology & Neurotherapeutics, University of Texas Southwestern, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Background:
Despite the introduction of new medicines to treat epilepsy over the last 50 years, the number of patients with poorly-controlled seizures remains unchanged. Metabolism-based therapies are an underutilized treatment option for this population. We hypothesized that two different means of systemic ketosis, the ketogenic diet and intermittent fasting, would differ in their acute seizure test profiles and mitochondrial respiration.
Methods:
Male NIH Swiss mice (aged 3-4 weeks) were fed for 12-13 days using one of four diet regimens: ketogenic diet (KD), control diet matched to KD for protein content and micronutrients (CD), or CD with intermittent fasting (24 h feed/24 h fast) (CD-IF), tested post-feed or post-fast. Mice were subject to the 6 Hz threshold test or, in separate cohorts, after injection of kainic acid in doses based on their weight (Cohort I) or a uniform dose regardless of weight (Cohort II). Mitochondrial respiration was tested in brain tissue isolated from similarly-fed seizure-naïve mice.
Results:
KD mice were protected against 6 Hz-induced seizures but had more severe seizure scores in the kainic acid test (Cohorts I & II), the opposite of CD-IF mice. No differences were noted in mitochondrial respiration between diet regimens.
Interpretation:
KD and CD-IF do not share identical antiseizure mechanisms. These differences were not explained by differences in mitochondrial respiration. Nevertheless, both KD and CD-IF regimens protected against different types of seizures, suggesting that mechanisms underlying CD-IF seizure protection should be explored further.
Insights
The ketogenic diet (KD) and intermittent fasting (IF) protect against different seizure types in mice, with no changes in mitochondrial respiration. Further research into IF mechanisms for seizure control is recommended.
Area of Science:
- Neuroscience
- Metabolic Disorders
- Dietary Interventions
Background:
- Epilepsy treatment remains a challenge, with many patients experiencing poorly-controlled seizures despite new medications.
- Metabolism-based therapies, such as the ketogenic diet and intermittent fasting, represent underutilized options for epilepsy management.
Purpose of the Study:
- To investigate the distinct effects of the ketogenic diet (KD) and intermittent fasting (IF) on seizure control and mitochondrial respiration.
- To compare the acute seizure test profiles of KD and IF in a mouse model.
Main Methods:
- Male NIH Swiss mice were assigned to four diet regimens: KD, control diet (CD), or CD with intermittent fasting (CD-IF) tested post-feed or post-fast.
- Mice underwent either a 6 Hz threshold seizure test or kainic acid-induced seizures (two dosing methods).
- Mitochondrial respiration was assessed in brain tissue from seizure-naïve mice on the same diets.
Main Results:
- Ketogenic diet (KD) protected against 6 Hz-induced seizures but worsened kainic acid-induced seizures.
- Intermittent fasting (IF) showed the opposite effect, protecting against kainic acid-induced seizures while not protecting against 6 Hz-induced seizures.
- No significant differences in mitochondrial respiration were observed across the diet regimens.
Conclusions:
- Ketogenic diet (KD) and intermittent fasting (IF) employ different mechanisms for seizure protection.
- These distinct mechanisms are not attributable to alterations in mitochondrial respiration.
- Both KD and IF demonstrate efficacy against specific seizure types, highlighting the need for further investigation into the mechanisms of IF-mediated seizure protection.
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