Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury

Objectives: To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment. Design: Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board–approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009). Setting: Thirty-six–bed PICU in a university-affiliated children's hospital. Patients and Subjects: Twelve children 2–18 years old after severe traumatic brain injury and five age-matched control subjects. Intervention: Probenecid (25 mg/kg) and N-acetylcysteine (140 mg/kg) or placebo administered via naso/orogastric tube. Measurements and Main Results: The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation. Conclusions: This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Supported, in part, by the National Institutes of Health grants R01 NS069247 (to Drs. Empey, Bell, and Clark), 1TL1 TR001858-01 (to Dr. Hagos). Mr. Hagos, Drs. Empey, Poloyac, Bayir, Bell, and Clark received support for article research from the National Institutes of Health (NIH). Mr. Hagos received funding from NIH and University of Pittsburgh Clinical and Translational Science Institute. Mr. Hagos, Drs. Empey, and Bell disclosed off-label product use of probenecid and N-acetylcysteine for pediatric traumatic brain injury. Drs. Empey's, Kochanek's, and Bell's institutions received funding from the NIH. Dr. Kochanek received funding from Society of Critical Care Medicine and World Federation of Pediatric Intensive and Critical Care Societies (Editor-in-Chief of Pediatric Critical Care Medicine) and he has served as an expert witness on a number of cases and has given numerous lectures as a guest professor. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: clarkrs@ccm.upmc.edu; pempey@pitt.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

https://ift.tt/2ryzkeg