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

doi:10.1016/j.isci.2021.103108

Traumatic brain injury induces region-specific glutamate metabolism changes as measured by multiple mass spectrometry methods

iScience. 2021 Sep 9;24(10):103108. doi: 10.1016/j.isci.2021.103108. eCollection 2021 Oct 22.

Authors

James L Sowers^{1

2

3}, Mark L Sowers^{1

4}, Alexander S Shavkunov⁴, Bridget E Hawkins^{5

3

6}, Ping Wu^{2

3}, Douglas S DeWitt^{5

3}, Donald S Prough^{5

3}, Kangling Zhang^{4

3}

Affiliations

¹ MD-PhD Combined Degree Program, University of Texas Medical Branch, Galveston, TX 77555, USA.
² Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston, TX 77555, USA.
³ The Moody Project for Translational Traumatic Brain Injury Research, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁴ Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁵ Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA.
⁶ Research Innovation and Scientific Excellence (RISE) Center, School of Nursing, University of Texas Medical Branch, Galveston, TX 77555, USA.

Abstract

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.

Keywords: Metabolomics; Molecular physiology; Neuroscience.