Inhibition of the advanced glycation end-product (RAGE) pathway prevents post-cardiac arrest sequels in rabbits

The post-cardiac arrest syndrome is characterized by an aseptic inflammatory response triggered by danger associated molecular patterns (DAMPs). Among DAMPs, high mobility group box-1 (HMGB1) is one of the major promoters of innate immunity after cardiac arrest. Previous work has shown that its “chelation” by glycyrrhizin resulted in a neuroprotective effect. However, the receptor by which HMGB1 could exert its deleterious effect still need to be determined in this situation. The aim of this study was to investigate whether the inhibition of the HMGB1 receptor for advanced glycation end-product (RAGE) could produce neurological benefits after cardiac arrest in rabbits. Anesthetized rabbits underwent 10 minutes of ventricular fibrillation. After cardiopulmonary resuscitation, they randomly received an administration of either saline (control group; n = 8) or FPS-ZM1 (1 mg/kg, i.v.), a specific inhibitor of the RAGE pathway (FPS group; n = 8). After animal awakening, survival and neurological dysfunction were assessed during 3 days. After cardiac arrest, the neurological dysfunction score was significantly lower in FPS vs. control group (37 ± 9% vs. 78 ± 6 at day 1 and 24 ± 10% vs. 92 ± 8 at day 3 in control and FPS groups, respectively; both P < 0.05). Histopathological analyses also showed reduced neuronal damages in FPS vs. control groups (96 ± 11 vs. 39 ± 14 degenerating neurons/field in the brain, respectively). An increase in interleukin (IL)-6 blood levels was observed in both groups with no significant difference among groups after cardiac arrest (203 ± 29 vs. 142 ± 44 pg/mL at t = 180 min post-resuscitation in control and FPS groups, respectively). Our findings support that the inhibition of the RAGE pathway by FPS-ZM1 results in neuroprotective effects without significant effect on IL-6 blood levels. It could explain a part of the deleterious effect of HMGB1 after cardiac arrest.