A study of the anticonvulsant effect of the ketogenic diet (KD) in adolescent rats, at Emory University and other centers, found that the hippocampus responds by inducing mitochondrial biogenesis, enhancing metabolic gene expression, and increasing energy reserves. The density of mitochondrial profiles in the dentate gyrus was increased by 46%. An energy preservation hypothesis leading to alternative energy stores is proposed for the diet, especially important for the survival and function of GABAergic interneurons under stressful conditions. [1]

COMMENT. These authors propose that chronic ketosis activates a genetic program that leads to mitochondrial biogenesis in the hippocampus, resulting in enhanced energy stores. Sustained ATP levels during stress allow membrane stabilization and elevation of the seizure threshold. Alternative mechanisms of action of the ketogenic diet previously proposed have included the anesthetic effects of ketone bodies, the associated acidosis, and changes in electrolytes. In clinical balance studies performed at the Mayo Clinic, where the diet was first introduced [2], an anticonvulsant effect was unrelated to diuresis, independent of acidosis and ketosis, and was correlated with an increased urinary excretion and negative balance of sodium and potassium [3]. In animal studies, an anticonvulsant effect of a high fat, low carbohydrate diet was demonstrated in mice with a seizure threshold first lowered by water intoxication and hypoelectrolytemia; seizure susceptibility was not modified by a similar diet in normal animals (idem/ibidem 1964;107:593-604). [4]