Ketogenic diet prevents alterations in brain metabolism in young but not adult rats after traumatic brain injury - PubMed (original) (raw)

Ketogenic diet prevents alterations in brain metabolism in young but not adult rats after traumatic brain injury

Ying Deng-Bryant et al. J Neurotrauma. 2011 Sep.

Abstract

Previous studies have shown that the change of cerebral metabolic rate of glucose (CMRglc) in response to traumatic brain injury (TBI) is different in young (PND35) and adult rats (PND70), and that prolonged ketogenic diet treatment results in histological and behavioral neuroprotection only in younger rat brains. However, the mechanism(s) through which ketones act in the injured brain and the biochemical markers of their action remain unknown. Therefore, the current study was initiated to: 1) determine the effect of injury on the neurochemical profile in PND35 compared to PND70 rats; and 2) test the effect of early post-injury administration of ketogenic diet on brain metabolism in PND35 versus PND70 rats. The data show that alterations in energy metabolites, amino acid, and membrane metabolites were not evident in PND35 rats on standard diet until 24 h after injury, when the concentration of most metabolites was reduced from sham-injured values. In contrast, acute, but transient deficits in energy metabolism were measured at 6 h in PND70 rats, together with deficits in N-acetylaspartate that endured until 24 h. Administration of a ketogenic diet resulted in significant increases in plasma β-hydroxybutyrate (βOHB) levels. Similarly, brain βOHB levels were significantly elevated in all injured rats, but were elevated by 43% more in PND35 rats compared to PND70 rats. As a result, ATP, creatine, and phosphocreatine levels at 24 h after injury were significantly improved in the ketogenic PND35 rats, but not in the PND70 group. The improvement in energy metabolism in the PND35 brains was accompanied by the recovery of NAA and reduction of lactate levels, as well as amelioration of the deficits of other amino acids and membrane metabolites. These results indicate that the PND35 brains are more resistant to the injury, indicated by a delayed deficit in energy metabolism. Moreover, the younger brains revert to ketones metabolism more quickly than do the adult brains, resulting in better neurochemical and cerebral metabolic recovery after injury.

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Figures

FIG. 1.

FIG. 1.

Representative (A) 1H-NMRS and (B) 31P-NMRS spectra of chloroform–methanol extract of ipsilateral hemisphere from PND35 rats. (A) Peak assignment with the chemical shift scale set relative to trimethylsilyl propionate (TSP) at 0 ppm; (B) peak assignment with the chemical shift scale set relative to glycerophosphorylcholine (GroPChol) at −0.13 ppm. The following peaks assignments were made from the NMR spectrum: (A) _myo_-inositol (Inos), 4.06 ppm; glycine (Gly), 3.56 ppm; taurine (Tau), 3.44 ppm; choline (Chol), 3.20 ppm; phosphocreatine (PCr), 3.05 ppm; creatine (Cr), 3.04 ppm; aspartate (Asp), 2.82 ppm; glutamine (Gln), 2.46 ppm; glutamate (Glu), 2.36 ppm; γ-aminobutyric acid (GABA), 2.31 ppm; _N_-acetyl aspartate (NAA), 2.02 ppm; alanine (Ala), 1.48 ppm; lactate (Lac), 1.33 ppm; (B) phosphorylethanolamine (PEtn), 3.86 ppm; phosphorylcholine (PChol), 2.63 ppm; glycerophosphorylethanolamine (GroPEtn), 0.81 ppm; glycerophosphorylcholine (GroPChol), −0.13 ppm; PCr, −3.12 ppm; (γ, α, β)-ATP, (-5.80, −10.92, −21.45) ppm; β-ADP, −6.11 ppm; nicotinamide adenine dinucleotides (NAD), −11.37 ppm.

FIG. 2.

FIG. 2.

Cerebral energy metabolite concentrations in PND35 rats on standard diet at 6 and 24 h after CCI injury compared to sham-injured (6 and 24 h sham data were pooled because there was no significant effect of time among the sham groups) rats on standard diet. All values are expressed as μmol per gram of sample dried protein pellet. Box plots: the horizontal line inside the box represents the median; the area above this line represents the 75th percentile of a variable; the area below this line represents the 25th percentile of a variable; the small horizontal markers above and below the box represent the maximal and minimal values respectively. *p<0.05, compared to sham-injured values with standard diet (control); #p<0.05, compared to CCI-injured values with standard diet at 6 hr post-injury.

FIG. 3.

FIG. 3.

Cerebral amino acids (A) and membrane metabolite concentrations (B) in PND35 rats on standard diet at 6 and 24 h after CCI injury compared to sham-injured rats (6 and 24 h sham data were pooled because there was no significant effect of time among the sham groups) on standard diet. All values are expressed as μmol per gram of sample dried protein pellet. Box plots: the horizontal line inside the box represents the median; the area above this line represents the 75th percentile of a variable; the area below this line represents the 25th percentile of a variable; the small horizontal markers above and below the box represent the maximal and minimal values respectively. *p<0.05, compared to sham-injured values with standard diet; #p<0.05, compared to CCI-injured values with standard diet at 6 h post-injury.

FIG. 4.

FIG. 4.

Representative 1H-NMRS spectra of brain β-hydroxybutyrate levels in both standard (A, B) and ketogenic fed (C) PND35 rats. (A) Full spectra width 1H-NMRS spectrum from a standard-fed, PND35 injured rat. (B) Magnified 1H-NMRS spectrum from (A) between 1.19 ppm and 1.51 ppm. (C) Similarly magnified 1H-NMRS spectrum to (B) from a ketogenic fed, PND35injured rat. (Table) Brain levels of β-hydroxybutyrate are expressed as mean±SD (μmol per gram of sample dry protein pellet).

FIG. 5.

FIG. 5.

The effect of ketogenic diet on injured brain energy metabolite concentrations. Ketogenic diet metabolite values ([Metabolites]KG DIET) are expressed as a percent change from standard diet values ([Metabolite]SD) at 6 hr (gray bars) and 24 h (black bars) after CCI injury in both (A) PND35 and (B) PND70 rats. #p<0.05, compared to standard-fed, injured rats.

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