Enhancement of the liver's neuroprotective role ameliorates traumatic brain injury pathology

Traumatic brain injury (TBI) is a pervasive problem worldwide for which no effective treatment is currently available. Although most studies have focused on the pathology of the injured brain, we have noted that the liver plays an important role in TBI. Using two mouse models of TBI, we found that the enzymatic activity of hepatic soluble epoxide hydrolase (sEH) was rapidly decreased and then returned to normal levels following TBI, whereas such changes were not observed in the kidney, heart, spleen, or lung. Interestingly, genetic downregulation of hepatic Ephx2 (which encodes sEH) ameliorates TBI-induced neurological deficits and promotes neurological function recovery, whereas overexpression of hepatic sEH exacerbates TBI-associated neurological impairments. Furthermore, hepatic sEH ablation was found to promote the generation of A2 pheno-type astrocytes and facilitate the production of various neuroprotective factors associated with astrocytes following TBI. We also observed an inverted V-shaped alteration in the plasma levels of four EET (epoxyeicosatrienoic acid) isoforms (5,6-, 8,9- ,11,12-, and 14,15- EET) following TBI which were negatively correlated with hepatic sEH activity. However, hepatic sEH manipulation bidirectionally regulates the plasma levels of 14,15- EET, which rapidly crosses the blood-brain barrier. Additionally, we found that the application of 14,15- EET mimicked the neuroprotective effect of hepatic sEH ablation, while 14,15-epoxyeicosa- 5(Z)- enoic acid blocked this effect, indicating that the increased plasma levels of 14,15- EET mediated the neuroprotective effect observed after hepatic sEH ablation. These results highlight the neuroprotective role of the liver in TBI and suggest that targeting hepatic EET signaling could represent a promising therapeutic strategy for treating TBI.

Automated summary

Traumatic brain injury (TBI) is a global problem with no effective treatment. The liver is found to play an important role in TBI, as demonstrated by decreased hepatic soluble epoxide hydrolase (sEH) activity following TBI. Hepatic Ephx2 downregulation improves TBI-induced neurological deficits, while overexpression of hepatic sEH exacerbates TBI-associated impairments. Hepatic sEH ablation promotes generation of neuroprotective factors and alters plasma levels of EET, which mediate the neuroprotective effect observed after hepatic sEH ablation. Targeting hepatic EET signaling may be a promising therapeutic strategy for TBI.