ABSTRACT
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.
Subject(s)
Brain Injuries/therapy , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Ketones/metabolism , Ketones/pharmacology , Age Factors , Aging/drug effects , Aging/physiology , Animals , Brain Injuries/pathology , Brain Injuries/physiopathology , Cerebral Cortex/growth & development , Disease Models, Animal , Energy Metabolism/drug effects , Energy Metabolism/physiology , Fluoresceins , Food, Formulated , Hippocampus/growth & development , Hippocampus/metabolism , Hippocampus/physiopathology , Ketones/therapeutic use , Lactic Acid/blood , Male , Nerve Degeneration/metabolism , Nerve Degeneration/prevention & control , Nerve Degeneration/therapy , Organic Chemicals , Rats , Rats, Sprague-Dawley , Treatment OutcomeABSTRACT
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 beta-hydroxybutyrate (betaHB). Arterio-venous differences were used to determine global cerebral uptake of betaHB and production of 14CO2 from [14C]3-betaHB 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 betaHB showed no significant increase in cerebral uptake of betaHB or 14CO2 production. Increasing arterial betaHB concentrations 2.9-fold with 3 h of betaHB infusion failed to increase cerebral uptake of betaHB or 14CO2 production in adult sham animals. Only CCI animals that received a 3-h betaHB infusion showed an 8.5-fold increase in cerebral uptake of betaHB and greater than 10.7-fold increase in 14CO2 production relative to sham betaHB-infused animals. The TBI-induced 20% decrease in ipsilateral cortical ATP concentration was alleviated by 3 h of betaHB infusion beginning immediately after CCI injury.
