UCF-101 Improves Long-Term Cognitive Dysfunction in Septic Encephalopathy Via Regulating UCH-L1 Activity

Background: Recent studies have confirmed that sepsis could induce long-term brain neurodegenerative change, manifested as hyperphosphorylation of Tau protein and deposition of Aβ, which could be regulated by deubiquitination enzyme UCH-L1. Because Omi/HtrA2 serine protease is activated in sepsis, and UCH-L1 is one of its natural substrates, the Omi/HtrA2-specific inhibitor UCF-101 should increase UCH-L1 concentration. Therefore, we hypothesized that UCF-101 might increase UCH-L1 concentration and activity in sepsis, thereby improving long-term cognitive dysfunction in sepsis-associated encephalopathy.Methods: In vivo experiments, CLP model and UCF-101 intervention were used to study neuroinflammation and neurodegenerative changes, detect UCH-L1 expression level and ubiquitin hydrolase activity, and verify the therapeutic effect of UCF-101 on long-term cognitive dysfunction in sepsis. Aβ 1-42 treated HT-22 cell line and UCF-101 intervention was also used for in vitro experiments. Ubiquitin hydrolase activity, Tau phosphorylation level and Aβ induced axonal injury were examined.Results: We observed that CLP significantly increased IL-1β, COX-2, and ICAM-1 levels in the prefrontal cortex of septic mice. The levels of Tau phosphorylation at Ser396 and Thr231 and Aβ formation were also significantly elevated. However, this effect was reversed by UCF-101. We verified UCH-L1 ubiquitin hydrolase activity was impaired in SAE and UCF-101 could sinificantly increase brain UCH-L1 level and ubiquitin hydrolase activity after CLP. In vitro experiments, we selected a moderate Aβ1–42 concentration, which did not affect HT-22 activity but lead to significant Tau phosphorylation. UCF-101 treatment could significantly decrease Tau hyper-phosphorylation. Immunofluorescence analysis also indicated UCF-101 could increase UCH-L1 level, affect free ubiquitin expression and improve axon cytoskeleton in HT-22 cells treated with the Aβ1–42 fragment. Finally, we examine the behavioral impact of UCF-101 using the open-field test and New Object Recognition (NOR) task. UCF-101 treated CLP animals showed almost normal crossing central zone time during open-field test and significant improvement of the ability to learn the NOR task compared with saline-treated CLP animals, overall indicating that long-term cognitive dysfunction was significantly reversed by UCF-101 treatment.Conclusions: We demonstrated, for the first time, that UCF-101, an Omi/HtrA2 inhibitor, alleviates long-term neurodegenerative changes induced by SAE by increasing UCH-L1 concentration and ubiquitin hydrolase activity. This may provide new ideas for the treatment of long-term cognitive dysfunction in SAE and other degenerative neurological diseases.