DNA FRAGMENTATION AND PROLONGED EXPRESSION OF C-FOS, C-JUN, AND HSP-70 IN KAINIC ACID-INDUCED NEURONAL CELL-DEATH IN TRANSGENIC MICE OVEREXPRESSING HUMAN CUZN-SUPEROXIDE DISMUTASE

Kainic acid (KA) neurotoxicity was examined in transgenic (Tg) mice ov erexpressing human CuZn-superoxide dismutase (SOD-1). The doses of KA required to produce seizures, the severity of the seizures, and the re gions damaged were similar in SOD-1 Tg and nontransgenic wild-type mic e. Intraperitoneal KA injection induced seizure-related neuronal damag e in the CA3 and CA1 regions of the hippocampus and in other regions o f the brain in both SOD-1 Tg and wild-type mice. These damaged neurons were labeled with the terminal deoxynucleotidyl transferase mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL) technique up to 72 h, although no significant difference in the number of TUNEL-pos itive neurons was observed between SOD-1 Tg and wild-type mice. In sit u hybridization showed that c-fos, c-jun, and hsp70 genes were express ed in the hippocampus, cortex, and other regions of the brain after KA treatment. The expression of these genes was maximal 1 to 4 h followi ng KA treatment but persisted longer in the hippocampus and other regi ons in SOD-1 Tg compared with wild-type mice; however, cell death in t he hippocampus, assessed using cresyl violet staining, was similar in SOD-1 Tg and wild-type mice. The data show that superoxide radicals mo dulate both immediate early gene and heat shock gene expression after KA-induced seizures. The prolonged expression of c-fos, c-jun, and hsp 70 in SOD-1 Tg compared with wild-type mice may indicate that hippocam pal neurons survive longer in SOD-1 Tg than in wild-type animals; howe ver, cell death as well as the seizure threshold, seizure severity and the pattern of regional vulnerability were not affected substantially by increased levels of SOD in the brain.