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.

Enterocyte Damage

“…It is possible that ischemic brain injury per se can impair again the small bowel function and structure. Indeed, Jeter et al (30) identified that patients with severe traumatic brain injury had lower plasma citrulline concentrations than patients with mild traumatic brain injury and controls, even in the absence of shock. In addition, Hernández et al (31) found that acute brain injury was associated with increased gut permeability compared with controls.…”

“…In our opinion, enterocyte biomarkers could be integrative markers of global ischemia, taking into account both duration and severity of ischemia, but this hypothesis requires further studies. Third, it is possible that ischemic brain injury itself is responsible for additional small bowel dysfunction (30,31). According to this hypothesis, patients with a poor neurological outcome, being those with the worst brain ischemia, could have more gut injury than patients with neurological recovery.…”

Hypothermia Decreases Cerebrospinal Fluid Asymmetric Dimethylarginine Levels in Children With Traumatic Brain Injury

“…Second, an assessment of L-arginine which was not determined in the current study, would have provided more insight into NOS function than ADMA itself. It has been demonstrated that TBI alters L-arginine levels and therefore it is possible that CSF L-arginine depletion may account for the observed altered ADMA levels (55, 56). Finally, the control subjects in this study were diagnosed with meningoencephalitis and pulmonary hypertension which potentially could have an influence on ADMA levels.…”

Current status of fluid biomarkers in mild traumatic brain injury

“…Jeter et al (2012) used chromatography and mass spectrometry to assess L-arginine and its metabolic products in the plasma (<24 h) of mTBI patients, but did not observe changes as compared to controls. The same group also assessed branched chain amino acids (BCAA) in plasma (<24) of mTBI patients (Jeter et al, 2013b).…”