Evidence of a role for
oxygen-derived
free radicals in the pathophysiology of endotoxic
shock has been found in animal models. However, the importance of
free radicals in chronic models of
bacterial infection has not been examined. In this study a novel nitrone radical spin trap is described and its activity in animal models of endotoxic
shock and chronic
bacteremia were explored.
MDL 101,002 is a cyclized variant of
alpha-phenyl N-tert-butyl nitrone (PBN), an established spin trap.
MDL 101,002 can react with
free radicals to form persistent adducts as demonstrated by electron paramagnetic resonance (EPR) spectroscopy. This agent is about 10 times more potent than PBN as an in vitro
antioxidant and scavenger of
hydroxyl radicals. In a rat endotoxic
shock model
MDL 101,002 (3-30 mg/kg, i.p.) administered 30 min prior to
endotoxin (30 mg/kg, i.p.) treatment reduced mortality in a dose-dependent manner.
Peroxide-enhanced chemiluminescence in hepatic homogenates from
endotoxin treated rats was elevated indicating that oxidative stress and
antioxidant depletion was increased. Importantly, treatment with
MDL 101,002 (30 mg/kg, i.
p.) 30 min prior to, and 120 min following
endotoxin, minimized the increase in chemiluminescence.
MDL 101,002 also reduced mortality in a model of chronic
bacteremia employing implantation of infected
fibrin clots into the peritoneal cavity of
gentamicin-treated leukopenic rats.
MDL 101,002 (2.5 mg/kg/hr) increased survival from 24% to 52% in these rats. These data are consistent with a role for
free radicals in the pathophysiology of endotoxic
shock and suggest
free radicals are also important mediators in chronic models of
sepsis.