Abstract
Sepsis-associated encephalopathy (SAE), a fatal complication of sepsis, contributes to cognitive impairment, high morbidity, and mortality. The molecular mechanism of hydrogen (H2) administration, as a promising strategy for the treatment of SAE, is still unclear. Peroxisome proliferator-activated receptor α (PPARα) is essential for alleviating symptoms and complications of SAE. However, little is known about the role of PPARα in SAE. This study was designed to evaluate the expression of PPARα in SAE and determine whether H2 can alleviate SAE through regulation of the cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling pathway and its downstream proteins via PPARα. After the injection of GW6471 (the PPARα inhibitor) or GW7647 (the PPARα agonist) or saline, C57BL/6 J mice were subjected to cecal ligation and puncture (CLP) or sham operation, then treated with 2% H2 by inhalation for 1 h after the operation. The 7-day survival rate was recorded, and the Y-maze test was used to assess cognitive function. Apoptotic cells were observed by TUNEL staining, and brain tissues were collected for pathological analysis by H&E staining. In addition, the levels of pro-inflammatory and anti-inflammatory cytokines (TNF-α, IL-6, IL-18, HMGB1, and IL-1β) were measured by ELISA and the expression of PPARα, CREB, BDNF and other neurotrophins, postsynaptic density protein of 95 kDa (PSD95) by Western blot. The relationship between PPARα and the CREB-BDNF signaling pathway was explored by coimmunoprecipitation (CO-IP). The results showed the expression of PPARα was decreased in SAE mice and that activation of PPARα in septic mice improved the survival rate and alleviated cognitive dysfunction. Furthermore, PPARα may have exerted anti-inflammatory and anti-apoptotic effects in septic mice. In addition, the GW6471 downregulated the expression of CREB, BDNF and other neurotrophins in SAE mice treated with H2. The expression of PSD95 was also downregulated and upregulated following the expression of PPARα. These results illustrated that H2 alleviates sepsis-induced brain injury in mice through the regulation of neurotrophins and hippocampal plasticity-related genes via PPARα by activating the CREB-BDNF signaling pathway.