Effect of a new synthetic free radical scavenger, 2-octadecyl ascorbic acid, on the mortality in mouse endotoxemia

Abstract

Oxygen-derived free radicals have been implicated as mediators of cellular injury in several model systems. In order to clarify the role of oxygen radicals in endotoxemia, we measured the serial lipid peroxide changes resulting from systemic radical reactions using a newly developed colormetric method. To determine the effect of a free radical scavenger on mortality in endotoxemia, a newly synthetic scavenger, 2-Octadecylascorbic acid (CV-3611), which overcome the detrimental properties (circulation half-life and cell penetration) of native SOD, was used in the model of mouse endotoxemia induced by the i. p. administration of E-coli endotoxin (10 mg/kg). Serial LPO (Lipid Peroxide) changes revealed significant elevations from the basal level of 4.52±0.79 nmol/ml to 10.5±2.04 nmol/ml at 2h (P<0.05), 12.0±2.44 nmol/ml at 8h (P<0.05), 32.8±12.5 nmol/mlat 12h(P<0.05) and 13.6±2.40 nmol/ml at 24h (P<0.05) following i. p. administration of E-coli. The circulation half life of CV-3611 was checked by a reversed-phase HPLC after 10 mg/kg s.c. administration. The level of CV-3611 reached peak levels of 0.54±0.10 μg/mml at 1h and 0.52±0.20 μg/ml at 2h then gradually decreased to the level of 0.04±0.004 μg/ml at 6h and to a non-detectable level at 24h after s.c. administration. Increased survival was seen at 2 days (P<0.001) after E-coli endotoxin administration in the CV-3611 treated group compared to the control group. These results suggest that oxygen derived free radicals contribute to mortality in mouse endotoxemia and that antioxidants such as CV-3611 may provide a new therapeutic avenue by improving survival of patients with gram-negative bacterial sepsis.