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Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet
Author(s) -
Bough Kristopher
Publication year - 2008
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2008.01846.x
Subject(s) - ketogenic diet , phosphocreatine , hippocampal formation , endocrinology , medicine , neurotransmission , hippocampus , anticonvulsant , biology , epilepsy , metabolism , energy metabolism , neuroscience , receptor
SummaryThe efficacy of the ketogenic diet (KD) develops gradually over a period of 1–3 weeks, suggesting that adaptive changes in gene expression are involved in its anticonvulsant effects. Previously, microarrays were employed to define patterns of gene expression in the hippocampus of rats maintained on either a KD or a control diet for 3 weeks. The density of mitochondria in hippocampal tissue was assessed by electron microscopy. Levels of selected energy metabolites, enzyme activities, and the effect of low glucose on synaptic transmission were also investigated in hippocampal tissue taken from either KD‐ or control‐fed animals. We found a coordinated up‐regulation of transcripts encoding energy metabolism enzymes and a dramatic 46% increase in the density of mitochondria observed in neuronal processes. These changes were accompanied by an increased phosphocreatine (PCr):creatine (Cr) energy‐store ratio. Consistent with heightened energy reserves, hippocampal synaptic transmission in KD‐fed animals was maintained ∼50% longer compared to controls after exposure to a mild metabolic stressor. Taken together, several lines of evidence indicate that the KD enhances energy production in the brain. As a consequence, brain tissue appears to become more resistant to metabolic stress. It is proposed . . . that the observed KD‐induced enhancements in energy metabolism help to compensate for the metabolic deficits exhibited (interictally) within epileptic foci and transient failures of gamma‐aminobutyric acid (GABA) ergic inhibition, which would otherwise favor the initiation and propagation of seizure activity .