Human Traumatic Brain Injury Alters Circulating L-Arginine and Its Metabolite Levels: Possible Link to Cerebral Blood Flow, Extracellular Matrix Remodeling, and Energy Status

Abstract

Altered cerebral blood flow, cell-matrix interactions, and energy metabolism are secondary pathologies contributing to outcome after traumatic brain injury (TBI). Because L-arginine serves as the precursor for metabolites that are critical to these processes, we measured their plasma levels using LC-MS/GC-MS. Samples were collected from healthy volunteers (n=20), and patients with mild TBI (n=18), severe TBI (n=20), or orthopedic injury without a TBI (n=15), within the first 24 hours of injury. Severe TBI levels of L-arginine, citrulline, ornithine, and hydroxyproline were significantly reduced compared to the other groups. In contrast, the levels of plasma creatine were significantly increased in severe TBI patients compared to healthy volunteers and orthopedic injury subjects. Of interest, the levels of creatine were found to be higher in severe TBI patients (GCS score ≤8) whose intracranial pressure (ICP) remained below 25 mm Hg throughout the 5-day monitoring period, compared to TBI patients (GCS score ≤8) who subsequently developed elevated ICP (≥25 mm Hg). The changes in L-arginine and its metabolite levels were not detected in subjects with mild TBI. The altered levels of arginine and its metabolites may contribute to secondary pathologies following severe TBI, and plasma levels of creatine may have prognostic value in identifying patients at risk for ICP elevation.