Exploring the Metabolic Impact of Traumatic Brain Injury in CCI Mouse Models: A Focus on Early and Prolonged Injury Responses

Traumatic brain injury (TBI) disrupts brain metabolism, which evolves over time and varies with the severity of the injury. Monitoring these metabolomic changes may reveal biomarkers indicating early damage, mechanisms of injury, and potentially help predict outcomes. This study used untargeted plasma metabolomics to investigate systemic time-dependent metabolic changes in mice exposed to controlled cortical impact (CCI) with or without replacement of a modified skull cap designed to reduce compensatory space for cerebral edema modelling a severe closed skull TBI, compared to sham controls. Male mice were subjected to CCI, CCI + CAP, or sham procedures comprised a scalp incision or a craniotomy. Plasma samples were collected at 4, 8, and 16 h, and 3 and 7 days after injury. Hydrophilic interaction liquid chromatography–mass spectrometry (HILIC-MS) was used to profile metabolites in all groups and time points, while ion-pair liquid chromatography–mass spectrometry (RPIPLC-MS) was used in CCI and sham mice at the early time points. The largest metabolic changes occurred at 8 h post-injury, distinguishing mice with CCI from sham controls. The early changes concerned metabolism of amino acids, energy, and nucleotide pathways, with metabolites such as succinate, phenylalanine, and cytidine showing significant changes. By 7 days, the metabolic patterns of the injured mice, especially CCI mice, had partially converged toward the sham state, although oxidative and mitochondrial disturbances persisted. The CCI + CAP mice had more pronounced and persistent metabolic disturbances compared to the CCI mice, which may reflect the effect of increased intracranial pressure post-injury. Plasma metabolomics can efficiently capture the evolving biochemical effects of TBI. The findings identified circulating metabolites that were associated with progression and severity of brain injury and provide a basis for future translational studies in human TBI.