Age-dependent use of alternative cerebral substrates during metabolic depression

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The acute metabolic changes after traumatic brain injury (TBI) are defined by the indiscriminate release of potassium and glutamate, transient elevation in local cerebral metabolic rate of glucose followed by prolonged glucose metabolic depression and reduction of ATP. During this period of depressed glucose metabolism there is an increase flux of glucose through the pentose phosphate, free radical production and activation of poly ADP-ribose polymerase (PARP) via DMA damage. The PARP-mediated DMA repair process requires NAD+. Depletion of the cytosolic NAD+ pool has been shown to decrease GAPDH (a key enzyme in the glycolytic pathway) activity. Under conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. While glucose remains the primary cerebral metabolic substrate under normal conditions, there are many physiological states during which the brain's reliance on glucose shifts towards ketone bodies, which are the only endogenously circulating alternative substrate that can significantly supplement cerebral metabolism. Recently, we have shown that exogenously administered R>- hydroxybutyrate is metabolized by the adult brain and TBI-induced decrease in ATP is alleviated (Prins et al., 2004). Our laboratory has also demonstrated the effectiveness of the ketogenic diet in reducing cortical contusion volume by 50% following focal TBI among postnatal day 30 (PND30) and PND45 rats (Prins et al 2005). The potential to utilize ketones as an alternative substrate decreases with cerebral maturation, suggesting that the younger brain possesses a greater ability to metabolize this substrate. The central hypothesis of this project is that TBI-induced changes in substrate transport and glucose biochemical processing promote age-dependent metabolism of alternative substrates during CMRglc depression. We believe that the use of ketone bodies as an alternative cerebral metabolic substrate offers exciting therapeutic potential following focal TBI in the developing brain and offers desperately needed treatment options for children with TBI.