Neuroprotectin D1 Protects Against Postoperative Delirium-like Behaviors in Aged Mice by Regulating Neuroinflammation Induced by Surgical Trauma

Background Postoperative delirium (POD) is the most common postoperative complication affected elderly patients, yet the underlying mechanism is elusive and without effective therapy. The neuroinflammation hypothesis has been emerging as the pathogenesis of POD. Recently, accumulative evidence has supported the role of specialized proresolving lipid mediators (SPMs) in regulating inflammation. NPD1, a novel member of SPMs, is identified with potent immune-resolvent and neuroprotective effect. We aimed to investigate the role of NPD1 in neuroinflammation and postoperative cognitive function with a mice model of POD. Methods Aged male C57BL/6 mice were subjected to laparotomy under isoflurane anesthesia with NPD1 prophylaxis. The general and memory behaviors were assessed by buried food test, open field test and Y maze test at 6, 9, and 24 hours after the surgery. Expression level of inflammatory cytokines were analyzed by ELISA. The permeability of blood-brain barrier (BBB) was detected by spectrophotometric quantification of extravascular dextran tracer from brain tissue extracts, and the expression of tight junction (TJ) associated proteins by Western blotting. The reactive states of astrocytes and microglia were examined by immunofluorescence. The protective effects of NPD1 was also evaluated through macrophage polarization by flow cytometry, using the bone marrow-derived macrophages cultures. Results NPD1 prophylaxis decreased the expression of pro-inflammatory cytokines and increased the expression of anti-inflammatory cytokines in peripheral blood, hippocampus and prefrontal cortex, and limited the leakage of BBB by increasing the expression of TJ associated proteins. Besides, NPD1 prevented the activation of microglia and astrocytes both in the hippocampus and prefrontal cortex, which resulted in improved general and memory function of mice. Furthermore, NPD1 treatment modulated the inflammatory cytokine profile and promoted the macrophage polarization toward M2 in LPS-stimulated macrophages. Conclusions These findings verify the anti-inflammatory and proresolving activities of NPD1 in the inflammatory milieu both in vivo and in vitro, and provide better insight into the pathophysiology and potential therapy for POD.