Dextran-coupled deferoxamine improves outcome in a murine model of head injury.
Tissue damage involving oxygen-derived free radicals may be greatly exacerbated by free, reactive iron, which acts as a catalyst in oxidative reactions. The effects of free iron can be attenuated by the administration of deferoxamine (DFO), an iron chelator. However, DFO has limited therapeutic utility because it has a short plasma half-life (approximately 5.5 min in mice) and produces profound hypotension upon intravenous infusion. These negative attributes have been circumvented by the covalent attachment of DFO to large polymers, such as dextran or hydroxyethyl starch. The ability of the dextran-conjugated DFO (DEX-DFO) to inhibit iron-catalyzed reactions with lipids was compared to that of the native molecule in an in vitro model of CNS lipid degradation in the presence of 200 microM ferrous iron. There was no difference between native DFO and the modified form. Modified and unmodified DFO were also compared for therapeutic efficacy in a murine model of head injury. Using a previously described "grip test" as a measure of neurologic impairment following injury, DEX-DFO, native DFO, and dextran were administered intravenously 3-5 min after injury. Dextran-DFO significantly decreased the incidence of severe neurologic impairment at dosage levels of 0.1 (n = 92), 1.0 (n = 76), and 10.0 (n = 80) mg/kg. Administration of native DFO or dextran had no effect at the same dosages and concentrations. These results suggest that the murine model of head injury contains a significant iron-dependent component that should be assessed in other models of neural injury.
Panter
S S
SS
Letterman Army Institute of Research, Blood Research Division, Presidio of San Francisco, California.
Braughler
J M
JM
Hall
E D
ED
D000818:Animals; D002614:Chelating Agents / Q000627:therapeutic use*; D006259:Craniocerebral Trauma / Q000188:drug therapy* / Q000378:metabolism; D003676:Deferoxamine / Q000627:therapeutic use*; D003911:Dextrans; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D051381:Rats
D002614:Chelating Agents; D003911:Dextrans; D007501:Iron; D003676:Deferoxamine