Blood-brain barrier, ion homeostatis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms.
The finding that epileptic seizures alter blood-brain barrier (BBB) properties has stimulated interest into the possibility that phenotypic changes in brain endothelium may constitute a pathological initiator leading to seizures. Recent evidence obtained from epileptic patients undergoing cortical resection, demonstrated abnormal expression of glucose transporter molecules (GLUT1), while [18F]deoxyglucose PET studies demonstrated regions of decreased glucose uptake and hypometabolism in seizure foci. The properties of other 'nonexcitable CNS cells' are also altered in epileptic tissue, and glial cells from epileptic brain displayed diminished capacity for ionic homeostasis; voltage-dependent mechanisms were primarily affected, increasing reliance on energy-dependent mechanisms. Diminished ion homeostasis together with increased metabolic demand of hyperactive neurons may further aggravate the neuropathological consequences of BBB loss of glucose uptake mechanisms. Since ketone bodies can provide an alternative to glucose to support brain energy requirements, it is hypothesized that one of the mechanisms of the ketogenic diet in epilepsy may relate to increased availability of beta-hydroxybutyrate, a ketone body readily transported at the BBB. This hypothesis is supported by the fact that the ketogenic diet is the treatment of choice for the glucose transporter protein syndrome and pyruvate dehydrogenase deficiency, both associated with cerebral energy failure and seizures.
Janigro
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Cerebravascular Research, Cleveland Clinic Foundation, OH 44195, USA. janigrd@ccf.org
D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D004827:Epilepsy / Q000178:diet therapy / Q000378:metabolism* / Q000503:physiopathology; D051272:Glucose Transporter Type 1; D006801:Humans; D007473:Ion Channels; D007657:Ketone Bodies / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*
D051272:Glucose Transporter Type 1; D007473:Ion Channels; D007657:Ketone Bodies; D009004:Monosaccharide Transport Proteins; C495677:SLC2A1 protein, human