Remimazolam Attenuates Lipopolysaccharide-Induced Inflammatory Responses in Macrophages

Remimazolam (Re) is an ultra-short-acting benzodiazepine used for intravenous sedation, general anesthesia, and intensive care unit sedation. Although benzodiazepines, including midazolam, possess anti-inflammatory properties and suppress macrophage activity, the impact of Re on macrophage-mediated immune responses remains uncertain. The purpose of this study was to investigate the effects of Re on lipopolysaccharide (LPS)-stimulated macrophage activation using thioglycolate-induced mouse peritoneal macrophages (TGC-macrophages). The findings demonstrated that Re significantly attenuated the production of proinflammatory cytokines, tumor necrosis factor α, and interleukin-6 by LPS-stimulated TGC-macrophages. Notably, this inhibitory effect on cytokine production remained unaffected by flumazenil, a specific antagonist of the γ-aminobutyric acid type A (GABAA), indicating that Re exerts its anti-inflammatory effects on macrophages through a mechanism independent of GABAA receptor signaling. In Re-treated macrophages, the expression levels of antigen presentation-related molecules, including CD86, a costimulatory molecule, and major histocompatibility complex class II, were significantly reduced following LPS stimulation. Conversely, Re did not affect the phagocytic capacity of TGC-macrophages, as evaluated by fluorescein isothiocyanate-labeled dextran, even at concentrations that inhibited inflammatory cytokine production and costimulatory molecule expression in LPS-activated TGC-macrophages. These findings suggest that Re exerts anti-inflammatory effects without suppressing essential innate immune functions, such as phagocytosis by macrophages.