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.
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.
Kondo
T
T
Department of Neurological Surgery, School of Medicine, University of California, San Francisco 94143, USA.
Sharp
F R
FR
Honkaniemi
J
J
Mikawa
S
S
Epstein
C J
CJ
Chan
P H
PH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003300:Copper; D053938:DNA Fragmentation; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005609:Free Radicals; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early; D016762:Genes, fos; D016758:Genes, jun; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D017403:In Situ Hybridization; D007608:Kainic Acid / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D010587:Phagocytosis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D015032:Zinc
D018690:Excitatory Amino Acid Agonists; D005609:Free Radicals; D018840:HSP70 Heat-Shock Proteins; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D013481:Superoxides; D003300:Copper; D013482:Superoxide Dismutase; D015032:Zinc; D007608:Kainic Acid