Molecular hydrogen alleviates brain injury and cognitive impairment in a chronic sequelae model of murine polymicrobial sepsis

Sepsis-related encephalopathy (SAE), which causes a series of brain injuries and long-term, potentially irreversible cognitive dysfunction, is closely associated with increased morbidity and mortality. Hydrogen (H2) is a new type of medical gas molecule that has been widely used in the treatment of various diseases in recent years. The aim of the present study was to explore the protective effects of H2 inhalation on brain injury and long-term cognitive impairment in an improved chronic septic mouse model. Male C57BL/6J mice were randomized into four groups: Control, Control + H2, SAE and SAE + H2. The SAE and Control models were established by intraperitoneal injection of human stool suspension or saline in mice. H2 (2%) was inhaled for 60 min at 1 h and 6 h after SAE or Control treatment. The survival rates were recorded for 14 days (days 1–14) and the Morris Water Maze was performed for 7 days (days 8–14). To assess the severity of the brain injury, hematoxylin and eosin staining, Nissl staining, Evans blue (EB) extravasation and the wet/dry weight ratio of brain tissue were detected 24 h after SAE or Control treatment. In addition, inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin 6 (IL-6), high-mobility group box 1 (HMGB1), as well as the protein levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), zonula occludens-1 (ZO-1) and Occludin, were measured 6, 12 and 24 h after SAE or Control treatment. The results showed that H2 treatment increased survival rates, mitigated cognitive impairment, reduced hippocampal histological damage, decreased EB and water content, and decreased the levels of TNF-α, IL-6, HMGB1, Nrf2, HO-1, ZO-1 and Occludin, as compared with the SAE group. These data revealed that 2% H2 could suppress brain damage and improve cognitive function in septic mice by inhibiting oxidative stress, inflammatory response and the sepsis-induced blood–brain barrier (BBB) disruption.