Fig. 9
Working hypothesis for OI-mediated therapeutic effect on POCD in aged mice. OI can be hydrolyzed to itaconate after administration, which may reverse anesthesia/surgery-induced gut dysbiosis to produce neuroprotective metabolites. OI may enter the brain parenchyma due to its high cell permeability and activate Nrf2 signaling to inhibit neuroinflammatory responses and restore neurogenesis by hydrolyzing into itaconate. These combined mechanisms contributed to cognitive improvement in aged mice with POCD. OI, 4-octyl itaconate; POCD, postoperative cognitive dysfunction; Nrf2, nuclear factor erythroid 2-related factor 2; ERK, extracellular signal-related kinases