Ciprofol more broadly suppresses selected inflammatory markers than propofol in LPS-induced sepsis-associated encephalopathy

To investigate and compare the anti-inflammatory and neuroprotective effects of ciprofol and propofol in lipopolysaccharide (LPS)-induced sepsis-associated encephalopathy(SAE). C57BL/6 N mice with LPS-induced SAE were treated with propofol(LP) or ciprofol(LC). Cognitive function was assessed by the Morris water maze (MWM) and novel object recognition (NOR) tests. Neuroinflammation and glial activation in the hippocampus were evaluated by histology, immunohistochemistry (IHC), immunofluorescence (IF), and RT-qPCR. Systemic and cellular inflammatory responses were measured by ELISA. In vitro, BV2 microglial cells were treated with LPS, LP, or LC, and their effects on neuronal viability were assessed in a co-culture system. Underlying mechanisms were explored by Western Blot and RT-qPCR. In vivo, both ciprofol and propofol produced comparable improvements in cognitive outcomes, and representative H&E- and Nissl-stained sections showed similar histological patterns. At the tested doses, ciprofol more broadly suppressed selected inflammatory markers. Systemically, ciprofol significantly reduced all three tested cytokines (TNF-α, IL-1β, and IL-6), whereas propofol significantly reduced TNF-α only. In the hippocampus, ciprofol produced greater reductions in Il-1β transcription and Iba-1-positive cells in the dentate gyrus. In vitro, ciprofol also produced greater reductions in selected proinflammatory mediators in BV2 cells. Mechanistically, ciprofol was associated with greater suppression of Nlrp3 mRNA, whereas the corresponding between-drug protein-level difference was not significant. In murine LPS-induced SAE, ciprofol and propofol produced comparable improvements in cognitive outcomes and similar histological observations, whereas ciprofol more broadly suppressed selected systemic and hippocampal inflammatory markers and was associated with greater Nlrp3 transcriptional suppression in BV2 cells at the tested doses or concentrations. These preclinical findings require confirmation in clinically relevant sepsis models and human studies before they can inform anesthetic selection in patients with sepsis.