Ketogenic Diet Prevents Alterations in Brain Metabolism in Young but not Adult Rats after Traumatic Brain Injury

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 beta-hydroxybutyrate (beta OHB) levels. Similarly, brain beta OHB 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.