REDUCTION OF CUZN-SUPEROXIDE DISMUTASE ACTIVITY EXACERBATES NEURONAL CELL INJURY AND EDEMA FORMATION AFTER TRANSIENT FOCAL CEREBRAL-ISCHEMIA

Apoptotic neuronal cell death has recently been associated with the de velopment of infarction after cerebral ischemia. In a variety of studi es, CuZn-superoxide dismutase (CuZn-SOD) has been shown to protect the brain from ischemic injury. A possible role for CuZn-SOD-related modu lation of neuronal viability is suggested by the finding that CuZn-SOD inhibits apoptotic neuronal cell death in response to some forms of c ellular damage. We evaluated this possibility in the model of transien t focal cerebral ischemia in mice bearing a disruption of the CuZn-SOD gene (Sod1). Homozygous mutant (Sod1 -/-) mice had no detectable CuZn -SOD activity, and heterozygous mutants (Sod1 +/-) showed a 50% decrea se compared with wild-type mice. Sod1 -/- mice showed a high level of blood-brain barrier disruption soon after 1 hr of middle cerebral arte ry occlusion and 100% mortality at 24 hr after ischemia. Sod1 +/- mice showed 30% mortality at 24 hr after ischemia, and neurological defici ts were exacerbated compared with wild-type controls. The Sod1 +/- ani mals also had increased infarct volume and brain swelling, accompanied by increased apoptotic neuronal cell death as indicated by the in sit u nick-end labeling technique to detect DNA fragmentation and morpholo gical criteria. These results suggest that oxygen-free radicals, espec ially superoxide anions, are an important factor for the development o f infarction by brain edema formation and apoptotic neuronal cell deat h after focal cerebral ischemia and reperfusion.