DNA fragmentation and Prolonged expression of c-fos, c-jun, and hsp70 in kainic acid-induced neuronal cell death in transgenic mice overexpressing human CuZn-superoxide dismutase

J Cereb Blood Flow Metab. 1997 Mar;17(3):241-56. doi: 10.1097/00004647-199703000-00001.


Kainic acid (KA) neurotoxicity was examined in transgenic (Tg) mice overexpressing human CuZn-superoxide dismutase (SOD-1). The doses of KA required to produce seizures, the severity of the seizures, and the regions damaged were similar in SOD-1 Tg and non-transgenic wild-type mice. Intraperitoneal KA injection induced seizure-related neuronal damage in the CA3 and CA1 regions of the hippocampus and in other regions of 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-positive neurons was observed between SOD-1 Tg and wild-type mice. In situ hybridization showed that c-fos, c-jun, and hsp70 genes were expressed in the hippocampus, cortex, and other regions of the brain after KA treatment. The expression of these genes was maximal 1 to 4 h following KA treatment but persisted longer in the hippocampus and other regions in SOD-1 Tg compared with wild-type mice; however, cell death in the hippocampus, assessed using cresyl violet staining, was similar in SOD-1 Tg and wild-type mice. The data show that superoxide radicals modulate both immediate early gene and heat shock gene expression after KA-induced seizures. The prolonged expression of c-fos, c-jun, and hsp70 in SOD-1 Tg compared with wild-type mice may indicate that hippocampal neurons survive longer in SOD-1 Tg than in wild-type animals; however, 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Brain / drug effects*
  • Brain / metabolism
  • Copper
  • DNA Fragmentation
  • Excitatory Amino Acid Agonists / toxicity*
  • Free Radicals
  • Gene Expression Regulation / drug effects*
  • Genes, Immediate-Early
  • Genes, fos
  • Genes, jun
  • HSP70 Heat-Shock Proteins / biosynthesis*
  • HSP70 Heat-Shock Proteins / genetics
  • Humans
  • Immediate-Early Proteins / biosynthesis*
  • Immediate-Early Proteins / genetics
  • In Situ Hybridization
  • Kainic Acid / toxicity*
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Neurons / drug effects*
  • Neurons / metabolism
  • Oxidative Stress
  • Phagocytosis
  • Proto-Oncogene Proteins c-fos / biosynthesis*
  • Proto-Oncogene Proteins c-jun / biosynthesis*
  • Recombinant Fusion Proteins / biosynthesis
  • Recombinant Fusion Proteins / physiology
  • Seizures / chemically induced
  • Seizures / genetics
  • Superoxide Dismutase / biosynthesis
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / physiology*
  • Superoxides / metabolism
  • Zinc


  • Excitatory Amino Acid Agonists
  • Free Radicals
  • HSP70 Heat-Shock Proteins
  • Immediate-Early Proteins
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Recombinant Fusion Proteins
  • Superoxides
  • Copper
  • Superoxide Dismutase
  • Zinc
  • Kainic Acid