Mass Spectrometric Imaging of Ceramide Biomarkers Tracks Therapeutic Response in Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a serious public health problem and the leading cause of death in children and young adults. It also contributes to a substantial number of cases of permanent disability. As lipids make up over 50% of the brain mass and play a key role in both membrane structure and cell signaling, their profile is of particular interest. In this study, we show that advanced mass spectrometry imaging (MSI) has sufficient technical accuracy and reproducibility to demonstrate the anatomical distribution of 50 μm diameter microdomains that show changes in brain ceramide levels in a rat model of controlled cortical impact (CCI) 3 days post injury with and without treatment. Adult male Sprague-Dawley rats received one strike and were euthanized 3 days post trauma. Brain MS images showed increase in ceramides in CCI animals compared to control as well as significant reduction in ceramides in CCI treated animals, demonstrating therapeutic effect of a peptide agonist. The data also suggests the presence of diffuse changes outside of the injured area. These results shed light on the extent of biochemical and structural changes in the brain after traumatic brain injury and could help to evaluate the efficacy of treatments.

Will Sirtuins Be Promising Therapeutic Targets for TBI and Associated Neurodegenerative Diseases?

“…Mitochondrial dysfunction is a fundamental pathogenic event in most neurodegenerative diseases. Findings from rat models of TBI have revealed that ceramide is the first lipid to accumulate in the mitochondria after TBI (Roux et al, 2016), suggesting it may serve as a therapeutic indicator (Barbacci et al, 2017). Ceramide accumulation causes mitochondrial dysfunction (Novgorodov et al, 2016), which is associated with increased mitochondrial fission and excessive ROS production (Zhao et al, 2018).…”

Sphingolipids in neurodegeneration (with focus on ceramide and S1P)

“…Neurodegeneration is associated with alteration of sphingolipid metabolism and composition. In acute injuries such as stroke, concussion, spinal cord injury (SCI), or traumatic brain injury (TBI), activation of SMases and glycosidases and upregulation of ceramide and glycolipid levels are among the first responses of the injured tissue (Abe et al, 2018; Barbacci et al, 2017; Brunkhorst et al, 2015; Gu et al, 2013; Horres and Hannun, 2012; Jones and Ren, 2016; Kubota et al, 1989; Novgorodov and Gudz, 2011; Ong et al, 2015; Roux et al, 2016; Sajja et al, 2018). C18:0 and C18:1 ceramide, typical neuronal ceramides synthesized by CerS1, are dysregulated within 24 h after the insult and can be used as biomarkers for TBI (Sajja et al, 2018).…”

Alzheimer's-associated upregulation of mitochondria-associated ER membranes after traumatic brain injury

“…This hypothesis is supported by our data on sphingolipid alterations after injury. Previous lipidomics studies in TBI have reported reductions in SM and increases in ceramides [13,66], speaking to elevated SMase activity. Indeed, multiple activators of SMase activity (such as tumor necrosis factor alpha [67], arachidonic acid [68] and glutamate [69]) are established components of TBI pathology.…”