An Animal Model for the Ketogenic Diet

Abstract

Summary The electrical stimulus necessary to produce a minimal convulsion in adult rats started rising 10 days after they were placed on a high‐fat diet, reaching a maximum at about 20 days. The convulsive threshold did not change in animals on a high‐carbohydrate diet. When the diet was changed from high‐fat to high‐carbohydrate, the electroconvulsive threshold reverted rapidly to prestudy levels. Biochemical studies revealed the high‐fat diet to be ketogenic as the blood concentrations of D‐β‐hydroxybutyrate and acetoacetate were elevated. Serum chloride, triglycerides, esterified fatty acids, and total lipids were also elevated, but the serum cholesterol was lowered. In brain, the only changes were elevations of D‐β‐hydroxybutyrate and sodium and lowering of the acetoacetyl Co A transferase activity. It is suggested that ketosis alters cerebral metabolism of glucose leading to an elevation in the electroconvulsive threshold. Résumé On a trouvé que le stimulus électrique nécessaire pour produire la plus petite convulsion chez des rats adultes commençait à s'élever à partir du 10ème jour après le début d'une diète riche en corps gras pour atteindre un maximum environ apres 20 jours. Le seuil convulsif ne changeait pas après une diète riche en hydrates de carbone. Lorsqu'on passait de la diète riche en corps gra à une diète riche en hydrates de carbone, le seuil électroconvulsif revenait rapidement aux niveaux habituels. Des études biochimiques ont démontré que la diéte riche en corps gras était cétogène puisqu'il y avait une augmentation des concentrations hématiques de D‐β‐hydroxybutyrate et d'acétoacetate. Le sérum chloride, les triglycérides, les acidesgras estérifiés et les lipides totaux étaient aussi élevés tandis que le cholesterol dans le serum etait diminue. Les seuls changements dans le cerveau etaient une elevation du D‐β‐hydroxybutyrate et du sodium, et une diminution de l'activite acétoacétyl CoA transferase. On suggère que la cétose modifie le metabolisme cerebral du glucose en amenant à une elevation du seuil électroconvulsif. Zusammenfassung 10 Tage nachdem ausgewachsene Ratten auf eine fettreiche Diät gesetzt worden waren, war erstmals ein grösserer elektrischer Reiz notwendig, um einen minimalen Krampf auszulösen als vorher. Die hierfür notwendige Reizstärke erreichte ihr Maximum nach etwa 20 Tagen. Unter kohlehydratreicher Diät veränderte sich die Krampfschwelle bei Tieren nicht. Wenn die Diät von fettreich auf kohlehydratreich umgestellt wurde, kehrte die Krampfschwelle rasch auf ihren Ausgangswert zuriick. Die fettreiche Diat erwies sich in biochemischen Untersuchungen als ketogen, da die Blutkonzentrationen von D‐β‐Hydroxybutyrat und Acetoacetat erhöht waren. Auch Serumchloride, Triglyceride, Fettsäureester und Gesamtlipide waren im Serum erhöht, Cholesterol erniedrigt. Im Gehirn bestanden die einzigen Veränderungen in einer Erhöhung von D‐β‐Hydroxbutyrat und Natrium sowie in einer Abnahme der Acetoacetyl CoA Transferase Aktivität. Es wird vermutet, dass die Ketose den cerebralen Glukosesto...

The Neuropharmacology of the Ketogenic Diet

“…However, in various ketogenic diet models, GABA levels were unchanged in mouse forebrain and cerebellum [36], mouse whole brain [38], mouse neocortex [41], and rat whole brain [42,43]. Although these data indicate that widespread increases in brain GABA levels do not occur in the ketogenic diet, they do not rule out the possibility of more specific local or regional changes in GABA content [40].…”

“…The shift in this transamination reaction would be expected to reduce aspartate, and substantial (23%) decreases in whole brain aspartate levels have been observed in mice receiving a ketogenic diet for 3 days [38], although this is not a consistent finding [39]. Anticonvulsant effects of the diet are not seen until after 7 to 10 days in rodents [42,58]. Whether there would be larger changes in aspartate or glutamate at later times is not known.…”

“…It seems plausible that the greater energy reserve would enhance the capacity of neurons to withstand metabolic challenges and could account for the ability of the diet to confer neuroprotection in models of neurodegenerative diseases or stroke [5]. It also has been proposed that effects of the ketogenic diet on brain energetics contribute to the seizure protection conferred by the diet [37,42], although there is little experimental support for this concept.…”

The Ketogenic Diet: Proposed Mechanisms of Action

“…11,12 That would mean that the brain of a person on the ketogenic diet would have more available energy (i.e., more ATP). That increase in available energy was postulated to have anticonvulsant effects.…”

“…Finally, it must be noted that brain levels of GABA have been measured in animals on a ketogenic diet, and widespread elevations have not been found, although studies are continuing and there is a possibility that there may be regional changes occurring in discrete areas. 4,11 …”