Sex differences in plasma endocannabinoids and related lipids before and after single and repeated mTBI: an...

Sex differences in mild traumatic brain injury (mTBI) symptoms and severity are documented in both initial clinical presentation and long-term outcomes. Convergent data have demonstrated that the long-term outcomes for female patients with mTBI are worse overall than those in male patients. Somewhat paradoxically, female patients are less likely to be admitted to the intensive care unit (ICU) and to have significantly shorter stays when admitted. Taken together, these data have suggested that female patients may appear to present symptoms that are considered less life-threatening after the initial injury than male patients; however, this lack of symptoms may contribute to their poorer long-term outcomes. Previous studies have identified protein-derived plasma biomarkers for mTBI; however, the effects of mTBI on lipid signaling molecules and metabolites in blood are largely unknown. Endogenous lipids (endolipids) such as the endocannabinoids (eCBs) and their congeners are endolipids with a range of signaling properties that are associated with promoting neuroprotective responses after mTBI in animal models. Previously, we demonstrated sex-dependent changes in neuroinflammation after repeated head injury, in which female patients had increased levels of neuroinflammatory markers. In this study, we examined genetic sex and timing effects on the plasma lipidome using a rat model of single and repeated mTBI. This exploratory lipidomics screen showed that a single head injury drives significantly more changes in plasma endolipids in male rats (32 %) than female rats (8%), whereas an additional head injury on the following day showed only 11% change in male rats but 15% in female rats. Key endolipids upregulated in male rats after the single-hit injury are precursors for resolvin molecules (eicosapentaenoic acid and docosapentaenoic acid), and this was absent in female rats. Given that this repeated injury mTBI model in rats showed greater longitudinal CNS damage in female rats, we hypothesize that the increases in endolipids in male rats but not female rats on the first day of injury are protective.