Neuroinflammation Plays a Potential Role in the MedullaOblongata after Moderate Traumatic Brain Injury in Mice as Revealed by Nontargeted Metabonomics Analysis.

Abstract

Moderate traumatic brain injury (mTBI) involves a series of complex pathophysiological processes in not only the area in direct contact with mechanical violence but also other brain regions far from the injury site, which may be important factors influencing subsequent neurological dysfunction or death. The medulla oblongata (MO) is a key area for the maintenance of basic respiratory and circulatory functions, whereas the pathophysiological processes after mTBI have rarely drawn the attention of researchers. In this study, we established a closed-head cortical contusion injury model, identified 6 different time points that covered the acute, subacute and chronic phases, and then used nontargeted metabolomics to identify and analyse the changes in differential metabolites (DMs) and metabolic pathways in the MO region. Our results showed that the metabolic profile of the MO region underwent specific changes over time: harmaline, riboflavin and dephospho-coenzyme A were identified as the key DMs and play important roles in reducing inflammation, enhancing antioxidation and maintaining homeostasis. Choline and glycerophospholipid metabolism were identified as the key pathways related to the changes in MO metabolism at different phases. In addition, we confirmed increases in the levels of inflammatory factors and the activation of astrocytes and microglia by Western blot and immunofluorescence staining, and these findings were consistent with the nontargeted metabolomics results. These findings suggest that neuroinflammation plays a central role in MO neuropathology after mTBI and provide new insights into the complex pathophysiologic mechanisms involved after mTBI.