Potentiation of excitotoxicity in transgenic mice overexpressing neuronal cyclooxygenase-2.
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.
Kelley
K A
KA
Neuroinflammation Research Laboratories, Department of Psychiatry, Brookdale Center for Developmental and Molecular Biology, Mount Sinai School of Medicine, New York, New York, USA.
Ho
L
L
Winger
D
D
Freire-Moar
J
J
Borelli
C B
CB
Aisen
P S
PS
Pasinetti
G M
GM
D000818:Animals; D015152:Blotting, Northern; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D015870:Gene Expression; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D017874:Immediate-Early Proteins; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D007608:Kainic Acid / Q000633:toxicity*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D009474:Neurons / Q000201:enzymology*; D009928:Organ Specificity / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D012640:Seizures / Q000139:chemically induced / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D018690:Excitatory Amino Acid Agonists; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D018698:Glutamic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D007608:Kainic Acid