OVEREXPRESSION OF SOD1 IN TRANSGENIC RATS PROTECTS VULNERABLE NEURONSAGAINST ISCHEMIC DAMAGE AFTER GLOBAL CEREBRAL-ISCHEMIA AND REPERFUSION

Transient global cerebral ischemia resulting from cardiac arrest is kn own to cause selective death in vulnerable neurons, including hippocam pal CA(1) pyramidal neurons. It is postulated that oxygen radicals, su peroxide in particular, are involved in cell death processes. To test this hypothesis, we first used in situ imaging of superoxide radical d istribution by hydroethidine oxidation in vulnerable neurons. We then generated SOD1 transgenic (Tg) rats with a five-fold increase in coppe r zinc superoxide dismutase activity. The Tg rats and their non-Tg wil d-type littermates were subjected to 10 min of global ischemia followe d by 1 and 3 d of reperfusion. Neuronal damage, as assessed by cresyl violet staining and DNA fragmentation analysis, was significantly redu ced in the hippocampal CA(1) region, cortex, striatum, and thalamus in SOD1 Tg rats at 3 d, as compared with the non-Tg littermates. There w ere no changes in the hippocampal CA(3) subregion and dentate gyrus, r esistant areas in both SOD1 Tg and non-Tg rats. Quantitative analysis of the damaged CA(1) subregion showed marked neuroprotection against t ransient global cerebral ischemia in SOD1 Tg rats. These results sugge st that superoxide radicals play a role in the delayed ischemic death of hippocampal CA(1) neurons. Our data also indicate that SOD1 Tg rats are useful tools for studying the role of oxygen radicals in the path ogenesis of neuronal death after transient global cerebral ischemia.