Surgery Upregulates High Mobility Group Box-1 and Disrupts the Blood-Brain Barrier causing Cognitive Dysfunction in Aged Rats

Aim Postoperative cognitive dysfunction (POCD) is a growing and largely underestimated problem without defined etiology. Herein, we sought to determine the relationship between cognitive decline, bloodbrain barrier (BBB) permeability, and inflammation, namely high mobility group box-1 (HMGB1), after surgery in aged rats. Methods Aged rats were randomly assigned as surgery group (n=45, splenectomy under general anesthesia), anesthesia (n=45, 2% isoflurane for 2h), and naive control (n=15). Markers of inflammation were measured in plasma and brain. Bloodbrain barrier ultrastructure and permeability were measured by transmission electron microscope (TEM) and IgG immunohistochemistry. Cognitive function was assessed in a reversal learning version of the Morris water maze (MWM). Results Surgical trauma under general anesthesia caused distinct changes in systemic and central proinflammatory cytokines. Levels of HMGB1 and the receptor for advanced glycation end products (RAGE) were significantly upregulated in the hippocampus of operated animals. Immunohistochemistry and TEM showed BBB disruption induced by surgery and anesthesia. These molecular changes were associated with cognitive impairment in latency with the MWM up to postoperative day 3. Conclusions HMGB1 and RAGE signaling appear pivotal mediators of surgery-induced cognitive decline and may contribute to the changes in BBB permeability after peripheral surgical trauma.