Background: Sepsis-associated encephalopathy (SAE) presents a significant clinical challenge, associated with increased mortality and healthcare expenses. Hyperbaric oxygen therapy (HBOT), involving inhaling pure or highly concentrated oxygen under pressures exceeding one atmosphere, has demonstrated neuroprotective effects in various conditions. However, the precise mechanisms underlying its protective actions against sepsisassociated brain injury remain unclear. This study aimed to determine whether HBOT protects against SAE and to elucidate the impact of the hypoxia-inducible factor-1 alpha (HIF-1 alpha) signaling pathway on SAE. Methods: The experiment consisted of two parts. In the first part, C57BL/6 J male mice were divided into five groups using a random number table method: control group, sham surgery group, sepsis group, HBOT + sepsis group, and HBOT + sham surgery group. In the subsequent part, C57BL/6 J male mice were divided into four groups: sepsis group, HBOT + sepsis group, HIF-1 alpha + HBOT + sepsis group, and HIF-1 alpha + sepsis group. Sepsis was induced via cecal ligation and puncture (CLP). Hyperbaric oxygen therapy was administered at 1 h and 4 h post-CLP. After 24 h, blood and hippocampal tissue were collected for cytokine measurements. HIF-1 alpha, TNF-alpha, IL1 beta, and IL-6 expression were assessed via ELISA and western blotting. Microglial expression was determined by immunofluorescence. Blood-brain barrier permeability was quantified using Evans Blue. Barnes maze and fear conditioning were conducted 14 days post-CLP to evaluate learning and memory. Results: Our findings reveal that CLP-induced hippocampus-dependent cognitive deficits coincided with elevated HIF-1 alpha and increased TNF-alpha, IL-1 beta, and IL-6 levels in both blood and hippocampus. Observable activation of microglial cells in the hippocampus and increased blood-brain barrier (BBB) permeability were also evident. HBOT mitigated HIF-1 alpha, TNF-alpha, IL-1 beta, and IL-6 levels, attenuated microglial activation in the hippocampus, and significantly improved learning and memory deficits in CLP-exposed mice. Additionally, these outcomes were corroborated by injecting a lentivirus that overexpressed HIF-1 alpha into the hippocampal region of the mice. Conclusion: HIF-1 alpha escalation induced peripheral and central inflammatory factors, promoting microglial activation, BBB impairment, and cognitive dysfunction. However, HBOT ameliorated these effects by reducing HIF1 alpha levels in Sepsis-Associated Encephalopathy.
