Exacerbation of delayed cell injury after transient global ischemia in mutant mice with CuZn superoxide dismutase deficiency

Background and Purpose-We have demonstrated that copper-zinc superoxide dis mutase (CuZn-SOD), a cytosolic isoenzyme of SODs, has a protective role in the pathogenesis of superoxide radical-mediated brain injury. Using mice be aring a disruption of the CuZn-SOD gene (Sod1), the present study was desig ned to clarify the role of superoxide anion in the pathogenesis of selectiv e vulnerability after transient global ischemia. Methods-Sod1 knockout homozygous mutant mice (Sod1 -/-) with a complete abs ence of endogenous CuZn-SOD activity, heterozygous mutant mice (Sod1 +/-) w ith a 50% decrease in the activity, and littermate wild-type mice (male, 35 to 45 g) were subjected to global ischemia. Since the plasticity of the po sterior communicating artery (PcomA) has been reported to influence the out come of hippocampal injury, we assessed the relation between the plasticity of PcomAs and the decrease of regional cerebral blood flow in global ische mia. Results-The fluorescence intensity of hydroethidine oxidation, a measuremen t of ethidium fluorescence for superoxide radicals, was increased in mutant mice 1 day after both 5 and 10 minutes of global ischemia, compared with w ild-type mice. Hippocampal injury in the PcomA hypoplastic brains showed si gnificant exacerbation in mutant mice compared with wild-type littermates 3 days after 5 minutes of global ischemia, although a marked difference was not observed at 1 day. Conclusions-These data suggest that superoxide radicals play an important r ole in the pathogenesis of delayed injury in the vulnerable hippocampal CAI subregion after transient global ischemia.