Although the adult brain primarily metabolizes glucose, the evidence from the starvation literature has demonstrated that the adult brain retains some potential to revert to ketone metabolism. This attribute has been exploited recently to shift the adult brain toward ketone metabolism after traumatic brain injury (TBI), resulting in increased cerebral uptake and oxidation of exogenously administered ketones and improved cerebral energy. The ability to utilize ketones as an alternative substrate decreases with cerebral maturation, suggesting that the younger brain has a greater ability to metabolize this substrate and may be more receptive to this therapy. It was hypothesized that the administration of ketones after TBI in the developing brain will decrease lesion size in an age-dependent manner. Postnatal day (PND) 17, 35, 45, and 65 rats were placed on either a standard or ketogenic (KG) diet after controlled cortical impact (CCI) injury. PND35 and PND45 KG-fed animals showed a 58% and 39% reduction in cortical contusion volume, respectively, at 7 days post-injury. The KG diet had no effect on contusion volume in PND17 and PND65 injured rats. Both PND35 and PND45 KG-fed groups revealed fewer Fluoro-Jade-positive cells in the cortex and hippocampus at 6 hr and showed earlier decreases in plasma lactate compared to standard-fed animals. The age-dependent ketogenic neuroprotection is likely related to age-related differences in cerebral metabolism of ketones and suggests that alternative substrate therapy has potential applications for younger head-injured patients.

There is growing evidence of the brain's ability to increase its reliance on alternative metabolic substrates under conditions of energy stress such as starvation, hypoxia and ischemia. We hypothesized that following traumatic brain injury (TBI), which results in immediate changes in energy metabolism, the adult brain increases uptake and oxidation of the alternative substrate b-hydroxybutyrate (bHB). Arterio-venous differences were used to determine global cerebral uptake of bHB and production of 14 CO 2 from [ 14 C]3-bHB 3 h after controlled cortical impact (CCI) injury. Quantitative bioluminescence was used to assess regional changes in ATP concentration. As expected, adult sham and CCI animals with only endogenously available bHB showed no significant increase in cerebral uptake of bHB or 14 CO 2 production. Increasing arterial bHB concentrations 2.9-fold with 3 h of bHB infusion failed to increase cerebral uptake of bHB or 14 CO 2 production in adult sham animals. Only CCI animals that received a 3-h bHB infusion showed an 8.5-fold increase in cerebral uptake of bHB and greater than 10.7-fold increase in 14 CO 2 production relative to sham bHB-infused animals. The TBI-induced 20% decrease in ipsilateral cortical ATP concentration was alleviated by 3 h of bHB infusion beginning immediately after CCI injury. Keywords: alternative substrates, b-hydroxybutyrate, metabolism, traumatic brain injury. Although glucose remains the primary cerebral metabolic substrate under normal conditions, there are many physiological states during which the brain's reliance on glucose shifts to alternative substrates (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976;Kries and Ross 1992;Vannucci and Vannucci 2000). In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al. 1986a) (Edmond et al. 1987). However, ketone bodies such as bHB are the only endogenously circulating alternative substrates that have been shown significantly to supplement cerebral metabolism (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976). In normally fed adult mammals bHB metabolism comprises less than 3% of total cerebral metabolism and bHB is present in low circulating concentrations (0.1 mM) with negligible uptake into the brain (Hawkins et al. 1971). However, upon increasing bHB arterial concentrations by starvation for 2 days or more, cerebral uptake is significantly enhanced (Hawkins et al. 1971). Increased cerebral uptake of bHB has also been shown during development (Hawkins et al. 1971;Dahlquist and Persson 1976), following starvation (Owen et al. 1967) and in diabetes (Kries and Ross 1992). The brain's ability to increase its reliance on bHB appears to be a common form of cerebral metabolic adaptation under conditions of insufficient glucose availability and developmental increases in cerebral energy demand.The evidence for the use of bHB by the brain under conditions of cerebral metabolic stress suggests a role for this alternative substrate in cerebral metabolism after ...