ABSTRACT
Patients treated for traumatic brain injury (TBI) are in metabolic crises because of the trauma and underfeeding. We utilized fractional gluconeogenesis (fGNG) to assess nutritional adequacy in ad libitum-fed and calorically-restricted rats following TBI. Male Sprague-Dawley individually housed rats 49 days of age were randomly assigned into four groups: ad libitum (AL) fed control (AL-Con, sham), AL plus TBI (AL+TBI), caloric restriction (CR) control (CR-Con, sham), and CR plus TBI (CR+TBI). From days 1-7 animals were given AL access to food and water containing 6% deuterium oxide (D2O). On day 8, a pre-intervention blood sample was drawn from each animal, and TBI, sham injury, and CR protocols were initiated. On day 22, the animals were euthanized, and blood was collected to measure fGNG. Pre-intervention, there was no significant difference in fGNG among groups (p ≥ 0.05). There was a significant increase in fGNG due to caloric restriction, independent of TBI (p ≤ 0.05). In addition, fGNG may provide a real-time, personalized biomarker for assessing patient dietary caloric needs.
ABSTRACT
The mechanisms underlying the complications of mild traumatic brain injury, including post-concussion syndrome, post-impact catastrophic death, and delayed neurodegeneration remain poorly understood. This limited pathophysiological understanding has hindered the development of diagnostic and prognostic biomarkers and has prevented the advancement of treatments for the sequelae of mild traumatic brain injury. We aimed to characterize the early electrophysiological and neurovascular alterations following repetitive mild traumatic brain injury and sought to identify new targets for the diagnosis and treatment of individuals at risk of severe post-impact complications. We combined behavioural, electrophysiological, molecular, and neuroimaging techniques in a rodent model of repetitive mild traumatic brain injury. In humans, we used dynamic contrast-enhanced MRI to quantify blood-brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury. Rats could clearly be classified based on their susceptibility to neurological complications, including life-threatening outcomes, following repetitive injury. Susceptible animals showed greater neurological complications and had higher levels of blood-brain barrier dysfunction, transforming growth factor ß (TGFß) signalling, and neuroinflammation compared to resilient animals. Cortical spreading depolarizations were the most common electrophysiological events immediately following mild traumatic brain injury and were associated with longer recovery from impact. Triggering cortical spreading depolarizations in mild traumatic brain injured rats (but not in controls) induced blood-brain barrier dysfunction. Treatment with a selective TGFß receptor inhibitor prevented blood-brain barrier opening and reduced injury complications. Consistent with the rodent model, blood-brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury. We provide evidence that cortical spreading depolarization, blood-brain barrier dysfunction, and pro-inflammatory TGFß signalling are associated with severe, potentially life-threatening outcomes following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of TGFß signalling may be a novel strategy in treating mild traumatic brain injury.
