Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet.
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.


CONCLUSIONS
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.
Bough
Kristopher J
KJ
Department of Pharmacology, Emory University, Atlanta, GA, USA. kbough96@yahoo.com
Wetherington
Jonathon
J
Hassel
Bjørnar
B
Pare
Jean Francois
JF
Gawryluk
Jeremy W
JW
Greene
James G
JG
Shaw
Renee
R
Smith
Yoland
Y
Geiger
Jonathan D
JD
Dingledine
Raymond J
RJ
D000818:Animals; D001923:Brain Chemistry; D004032:Diet; D004594:Electrophysiology; D004734:Energy Metabolism / Q000235:genetics; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism; D007657:Ketone Bodies / Q000097:blood; D008297:Male; D008660:Metabolism / Q000235:genetics; D008854:Microscopy, Electron; D008928:Mitochondria / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000178:diet therapy*; D009435:Synaptic Transmission / Q000502:physiology; D015854:Up-Regulation
D007657:Ketone Bodies; D005947:Glucose