Branched Chain Amino Acid Metabolism in Developmental Brain Injury: Putative Mechanisms and Therapeutic Potential

Abstract

Abstract – Background: Branched chain amino acid (BCAA) metabolism plays roles in various cellular processes, including energy homeostasis, anabolic signaling, and production of glutamate, the primary excitatory neurotransmitter. Emerging evidence also suggests BCAA metabolism has relationships to inflammatory and hypoxic cellular responses. Recent work in adult and adolescent clinical populations has suggested that BCAA dietary supplementation may improve outcomes associated with traumatic brain injury. Given these links, examining the putative mechanisms and potential therapeutic applications of modulating dietary BCAA content in the context of inflammatory and hypoxic developmental brain injury may reveal mechanisms for intervention in affected infants. Summary: Inflammatory and hypoxic brain injuries influence the dynamics of BCAA metabolism in the fetal brain. Inflammatory insults to the developing brain may increase BCAA catabolism downstream of the branched chain ketoacids (BCKAs). The effect of altered BCAA metabolism on the pathophysiology of inflammatory developmental brain injury is currently unclear but may play a role in microglial response. Hypoxic brain injury seems to increase BCAA concentration in the fetal brain, possibly because of re-amination of BCKAs to the parent BCAAs, or via increased protein breakdown during hypoxia. Key Messages: The apparent relationship between aberrant BCAA metabolism and inflammation or hypoxia warrants consideration of BCAA supplementation or restriction as a strategy for attenuating developmental brain injury that is associated with these pathologic events. This approach could entail alterations of maternal diet during pregnancy or the feeding of infant formula that is fortified with or restricted in BCAA. These types of interventions have been safely and effectively employed in cases of inborn errors of BCAA metabolism, suggesting feasibility in infant populations. Both in vitro and preclinical work is necessary to elucidate how BCAA supplementation or restriction may affect the sequelae of inflammatory and hypoxic developmental brain injury.