Traumatic brain injury induces region-specific glutamate metabolism changes as measured by multiple mass spectrometry methods
James L. Sowers,
Mark L. Sowers,
Alexander S. Shavkunov,
Bridget E. Hawkins,
Ping Wu,
Douglas S. DeWitt,
Donald S. Prough,
Kangling Zhang
Affiliations
James L. Sowers
MD-PhD Combined Degree Program, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston, TX 77555, USA; The Moody Project for Translational Traumatic Brain Injury Research, University of Texas Medical Branch, Galveston, TX 77555, USA; Corresponding author
Mark L. Sowers
MD-PhD Combined Degree Program, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
Alexander S. Shavkunov
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
Bridget E. Hawkins
Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA; The Moody Project for Translational Traumatic Brain Injury Research, University of Texas Medical Branch, Galveston, TX 77555, USA; Research Innovation and Scientific Excellence (RISE) Center, School of Nursing, University of Texas Medical Branch, Galveston, TX 77555, USA
Ping Wu
Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston, TX 77555, USA; The Moody Project for Translational Traumatic Brain Injury Research, University of Texas Medical Branch, Galveston, TX 77555, USA
Douglas S. DeWitt
Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA; The Moody Project for Translational Traumatic Brain Injury Research, University of Texas Medical Branch, Galveston, TX 77555, USA
Donald S. Prough
Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA; The Moody Project for Translational Traumatic Brain Injury Research, University of Texas Medical Branch, Galveston, TX 77555, USA
Kangling Zhang
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA; The Moody Project for Translational Traumatic Brain Injury Research, University of Texas Medical Branch, Galveston, TX 77555, USA
Summary: The release of excess glutamate following traumatic brain injury (TBI) results in glutamate excitotoxicity and metabolic energy failure. Endogenous mechanisms for reducing glutamate concentration in the brain parenchyma following TBI are poorly understood. Using multiple mass spectrometry approaches, we examined TBI-induced changes to glutamate metabolism. We present evidence that glutamate concentration can be reduced by glutamate oxidation via a “truncated” tricarboxylic acid cycle coupled to the urea cycle. This process reduces glutamate levels, generates carbon for energy metabolism, leads to citrulline accumulation, and produces nitric oxide. Several key metabolites are identified by metabolomics in support of this mechanism and the locations of these metabolites in the injured hemisphere are demonstrated by MALDI-MS imaging. The results of this study establish the advantages of multiple mass spectrometry approaches and provide insights into glutamate metabolism following TBI that could lead to improved treatment approaches.
