Novel low-molecular-weight superoxide dismutase mimic deferoxamine-manganese improves survival following hemorrhagic and endotoxic shock

The purpose of this study was to demonstrate the in vivo activity of the novel low-molecular-weight superoxide dismutase (SOD)-mimic deferoxamine-manganese (Def-Mn) in models of circulatory shock. Two forms of Def-Mn were examined: the pink-complex (NPC 14550) and the green complex (NPC 15823). Hemorrhagic shock was induced in rats (40 mmHg, 60 min) followed by autotransfusion of shed blood, and endotoxic shock (LPS, 200 μg/10g BW) was induced in mice. Significant lethality (ca. 20% survival rate at 24 hr) was observed in each model. Following hemorrhagic shock, NPC 14550 (10 mg/kg) increased the 24-hr survival rate to 48% (P=0.03), while NPC 15823 (10 mg/kg) did not significantly alter survival rate (30%, P > 0.05). Following endotoxin challenge, both NPC 14550 and NPC 15823 significantly improved the 24-hr survival rate to 68% (P≤0.001) and 55% (P=0.002), respectively. Bovine erythrocyte SOD and polyethylene glycol-SOD (Peg-SOD) also afforded significant protection in these models and, as anticipated, SOD afforded transient protection, while Peg-SOD provided significant protection for 24 hr and longer. Deferoxamine mesylate provided only transient protection. It is concluded that the SOD-mimic Def-Mn has beneficial effects following circulatory shock and, furthermore, these data provide additional evidence that the superoxide radical does play a role in these disorders.