Potentiation of excitotoxicity in transgenic mice overexpressing neuronal cyclooxygenase-2

Am J Pathol. 1999 Sep;155(3):995-1004. doi: 10.1016/S0002-9440(10)65199-1.

Abstract

In this study we describe the generation of a transgenic mouse model with neuronal overexpression of the human cyclooxygenase-2, h(COX)-2, to explore its role in excitotoxicity. We report that overexpression of neuronal hCOX-2 potentiates the intensity and lethality of kainic acid excitotoxicity in coincidence with potentiation of expression of the immediate early genes c-fos and zif-268. In vitro studies extended the in vivo findings and revealed that glutamate excitotoxicity is potentiated in primary cortico-hippocampal neurons derived from hCOX-2 transgenic mice, possibly through potentiation of mitochondrial impairment. This study is the first to demonstrate a cause-effect relationship between neuronal COX-2 expression and excitotoxicity. This model system will allow the systematic examination of the role of COX-2 in mechanisms of neurodegeneration that involve excitatory amino acid pathways.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Northern
  • Brain / enzymology
  • Brain / metabolism
  • Cells, Cultured
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • DNA-Binding Proteins / biosynthesis
  • Disease Models, Animal
  • Early Growth Response Protein 1
  • Embryo, Mammalian
  • Excitatory Amino Acid Agonists / toxicity*
  • Gene Expression
  • Glutamic Acid / toxicity
  • Humans
  • Immediate-Early Proteins*
  • Isoenzymes / biosynthesis*
  • Isoenzymes / genetics
  • Kainic Acid / toxicity*
  • Membrane Proteins
  • Mice
  • Mice, Transgenic / genetics*
  • Neurons / enzymology*
  • Organ Specificity / genetics
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Proto-Oncogene Proteins c-fos / biosynthesis
  • RNA, Messenger / biosynthesis
  • Seizures / chemically induced
  • Seizures / genetics
  • Transcription Factors / biosynthesis

Substances

  • DNA-Binding Proteins
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Excitatory Amino Acid Agonists
  • Immediate-Early Proteins
  • Isoenzymes
  • Membrane Proteins
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Transcription Factors
  • Glutamic Acid
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • PTGS1 protein, human
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Ptgs1 protein, mouse
  • Kainic Acid