Inhibiting High-Mobility Group Box 1 (HMGB1) Attenuates Inflammatory Cytokine Expression and Neurological Deficit in Ischemic Brain Injury Following Cardiac Arrest in Rats

Cardiac arrest (CA), if untreated for more than 5 min, can induce severe brain damage, the underlying mechanism of which is still unclear. Previous studies have indicated that high-mobility group box 1 (HMGB1), a nuclear protein implicated in several inflammatory disorders, is involved in the inflammatory processes following brain ischemia. However, the role of HMGB1 in brain dysfunction after CA is yet to be determined. In a rat CA model, HMGB1 protein expression was higher at 1, 3, and 7 days post-CA, compared to that in na < ve and sham-treated rats. Following injection of HMGB1 antibody (anti-HMGB1) into the cerebral ventricles, neurological deficit scores were significantly decreased in the CA group as compared to that in the na < ve and sham group. Nissl staining showed significant neuronal loss in the hippocampal CA1 region following CA, which was significantly attenuated by anti-HMGB1-treatment (10 and 50 mu g) in comparison with the vehicle-injected control. CA induced a significant increase in the levels of the cytokine interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) in the hippocampus as revealed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Treatment with anti-HMGB1 significantly inhibited IL-1 beta and TNF-alpha expression. Our study suggests that HMGB1 contributes significantly to CA-induced brain dysfunction and that inhibiting HMGB1 function and expression may be an effective therapeutic approach to CA-induced ischemic brain injury.