Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet

Kristopher J. Bough, Jonathon Wetherington, Bjørnar Hassel, Jean Francois Pare, Jeremy W. Gawryluk, James G. Greene, Renee Shaw, Yoland Smith, Jonathan D. Geiger, Raymond J. Dingledine

Research output: Contribution to journalArticle

287 Citations (Scopus)

Abstract

Objective: The full anticonvulsant effect of the ketogenic diet (KD) can require weeks to develop in rats, suggesting that altered gene expression is involved. The KD typically is used in pediatric epilepsies, but is effective also in adolescents and adults. Our goal was to use microarray and complementary technologies in adolescent rats to understand its anticonvulsant effect. Methods: Microarrays were used to define patterns of gene expression in the hippocampus of rats fed a KD or control diet for 3 weeks. Hippocampi from control- and KD-fed rats were also compared for the number of mitochondrial profiles in electron micrographs, the levels of selected energy metabolites and enzyme activities, and the effect of low glucose on synaptic transmission. Results: Most striking was a coordinated upregulation of all (n = 34) differentially regulated transcripts encoding energy metabolism enzymes and 39 of 42 transcripts encoding mitochondrial proteins, which was accompanied by an increased number of mitochondrial profiles, a higher phosphocreatine/creatine ratio, elevated glutamate levels, and decreased glycogen levels. Consistent with increased energy reserves, synaptic transmission in hippocampal slices from KD-fed animals was resistant to low glucose. Interpretation: These data show that a calorie-restricted KD enhances brain metabolism. We propose an anticonvulsant mechanism of the KD involving mitochondrial biogenesis leading to enhanced alternative energy stores.

Original languageEnglish (US)
Pages (from-to)223-235
Number of pages13
JournalAnnals of Neurology
Volume60
Issue number2
DOIs
StatePublished - Aug 1 2006

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Ketogenic Diet
Organelle Biogenesis
Anticonvulsants
Synaptic Transmission
Hippocampus
Gene Expression
Glucose
Phosphocreatine
Creatine
Mitochondrial Proteins
Enzymes
Glycogen
Energy Metabolism
Glutamic Acid
Epilepsy
Up-Regulation
Electrons
Pediatrics
Diet
Technology

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Bough, K. J., Wetherington, J., Hassel, B., Pare, J. F., Gawryluk, J. W., Greene, J. G., ... Dingledine, R. J. (2006). Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Annals of Neurology, 60(2), 223-235. https://doi.org/10.1002/ana.20899

Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. / Bough, Kristopher J.; Wetherington, Jonathon; Hassel, Bjørnar; Pare, Jean Francois; Gawryluk, Jeremy W.; Greene, James G.; Shaw, Renee; Smith, Yoland; Geiger, Jonathan D.; Dingledine, Raymond J.

In: Annals of Neurology, Vol. 60, No. 2, 01.08.2006, p. 223-235.

Research output: Contribution to journalArticle

Bough, KJ, Wetherington, J, Hassel, B, Pare, JF, Gawryluk, JW, Greene, JG, Shaw, R, Smith, Y, Geiger, JD & Dingledine, RJ 2006, 'Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet', Annals of Neurology, vol. 60, no. 2, pp. 223-235. https://doi.org/10.1002/ana.20899
Bough KJ, Wetherington J, Hassel B, Pare JF, Gawryluk JW, Greene JG et al. Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. Annals of Neurology. 2006 Aug 1;60(2):223-235. https://doi.org/10.1002/ana.20899
Bough, Kristopher J. ; Wetherington, Jonathon ; Hassel, Bjørnar ; Pare, Jean Francois ; Gawryluk, Jeremy W. ; Greene, James G. ; Shaw, Renee ; Smith, Yoland ; Geiger, Jonathan D. ; Dingledine, Raymond J. / Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet. In: Annals of Neurology. 2006 ; Vol. 60, No. 2. pp. 223-235.
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