Ketamine alleviated blood-brain barrier damage and microglia over-activation induced by SIRS via restricting cecum damage and HMGB1 release

Abstract Following systemic inflammatory response syndrome (SIRS), the brain is one of the most sensitive organs vulnerable to an external stressor. According to our previous study, ketamine had a protective effect on alleviating SIRS-associated neuronal necroptosis and cecal epithelial cell necroptosis by inhibiting the RIP1-RIP3-MLKL pathway. In this study, we further provided valid evidence that ketamine could safeguard the integrity of the blood-brain barrier (BBB), modulate microglia over-activation, and prevent neural network damage, resulting in relieving cerebral edema and improving system symptoms significantly. Simultaneously, cecum damage was partly reversed by ketamine intervention, which was attributed to a decrease in circulating high mobility group protein 1 (HMGB1). Interestingly, the result showed less cecum injury and relieved BBB disturbance in Rip3-/- mice. Furthermore, circulating HMGB1 content between Rip3-/- mice and mice with ketamine intervention significantly decreased. Moreover, anti-HMGB1 neutralizing antibody identically reversed BBB damage, indicating that cecum-promoted HMGB1 releases extravagated SIRS and BBB leakage. In addition, we clarified that cecectomy reduced serum HMGB1 release level and alleviated BBB damage and microglial activation. Altogether, our work shed light on the new view about the pathogenesis of SIRS, establishing the connection between cecum damage and BBB damage. Besides, we identified ketamine as a candidate to protect the brain from damage like BBB leakage and microglia over-activation, which attributed to the effect on alleviating cecum damage and decreasing circulation HMGB1 release. Our results provided a new theoretical view and therapeutic target for the application of ketamine in SIRS.