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Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet
Author(s) -
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.
Publication year - 2006
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20899
Subject(s) - ketogenic diet , mitochondrial biogenesis , anticonvulsant , hippocampal formation , endocrinology , glutamate receptor , phosphocreatine , medicine , hippocampus , biology , neurotransmission , mitochondrion , nrf1 , downregulation and upregulation , biochemistry , epilepsy , neuroscience , energy metabolism , gene , receptor
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. Ann Neurol 2006