Spatiotemporal characterization of GSTO1 inhibition in postoperative cognitive dysfunction: roles of hippocampal oxidative stress and neuroinflammation in aged mice

This preliminary study evaluated the time-dependent effects of hippocampal glutathione S-transferase omega 1 (GSTO1) inhibition on postoperative cognitive function, oxidative stress, and neuroinflammation in aged mice. Seventy-two aged male C57BL/6 mice were randomized into four groups (n = 18/group): Surgery+C1-27, Surgery+Vehicle, C1-27 only, and Control. Following Morris water maze pre-training, the respective interventions were performed. Spatial memory, hippocampal GSTO1 expression level, oxidative stress markers (ROS, MDA, GSH/GSSG ratio), the pro-inflammatory cytokines TNF-α, and total amyloid precursor protein (APP) immunoreactivity were dynamically evaluated at 6 h, 3 d, and 7 d post-modeling. Pharmacological GSTO1 inhibition combined with surgical trauma induced an acute decline in hippocampal GSTO1 expression at 6 h, along with a marked reduction of the GSH/GSSG ratio (P < 0.05). Early redox imbalance was temporally followed by gradual increases in ROS, MDA and TNF-α, as well as subregion-specific elevations in APP immunoreactivity in the hippocampus, with earlier onset in the CA3 and DG subregions and delayed increases in the CA1 region over the observational period. These cumulative microenvironmental alterations coincided with obvious spatial memory deficits at postoperative day 3 and day 7 (P < 0.05). Surgical trauma combined with pharmacological GSTO1 inhibition is associated with a temporally ordered sequence of pathological changes characterized by acute impairment of hippocampal antioxidant defense, progressive neuroinflammation, and subregion-predominant APP elevation with earlier onset in CA3 and DG, which correlate with exacerbated spatial memory deficits. These descriptive observational findings support an association between GSTO1-regulated microenvironmental homeostasis and perioperative cognitive decline, but do not establish causal relationships, establishing a foundation for future genetic and interventional causal validation.