The ketogenic diet changes metabolite levels in hippocampal extracellular fluid

Despite successful use of the previous termketogenic dietnext term (KD) for the treatment of drug-resistant epilepsy, its mechanism of action is unclear. After KD-feeding, increased plasma beta-hydroxybutyrate (BHB) previous termlevelsnext term appear to be important for protection against seizures. We hypothesized that the KD leads to metabolic previous termchangesnext term in the brain, which are reflected in the previous termhippocampalnext term extracellular fluid (hECF). CD1 mice were fed control or KD for 2-3 weeks since weaning. In-vivo microdialysis of hECF was used to measure the previous termlevelsnext term of glucose, lactate, as well as BHB under basal conditions and during 30 min stimulation with 60 mM K+, which was retrodialysed. The hECF BHB concentration in KD-fed mice was determined as 43.4 ± 10.1 μM using the zero-flow method and 50.7 + 5.5 μM based on in vitro-recovery. The total BHB concentration in brain homogenate from KD-fed mice was 180 nmoles/g. The intracellular BHB concentration is therefore estimated to be about 3-fold higher than the extracellular previous termlevel,next term which suggests that BHB in adolescent mouse brains may not be quickly metabolized. The basal hECF glucose concentration was 30% lower in KD-fed mice, indicating that glucose may be less important as an energy source. Lactate previous termlevelsnext term were similar in control and KD-fed mice. High potassium stimulation elevated lactate by 3-3.5-fold and decreased glucose by 40-50% in both previous termdietnext term groups, consistent with similar anaerobic and aerobic metabolism in both previous termdietnext term groups during high previous termhippocampalnext term activity. Overall, these data 1) defined the BHB concentration in the previous termhippocampalnext term extracellular fluid in KD-fed mice and 2) showed lower glucose metabolism compared to control previous termdietnext term-fed mice. This work will now enable other researchers to mimic the previous termhippocampalnext term extracellular environment in experiments aimed at deciphering the mechanisms of the KD