Neuronal cyclooxygenase-2 activity and prostaglandins PGE2, PGD2, and PGF2 alpha exacerbate hypoxic neuronal injury in neuron-enriched primary culture.
Cyclooxygenase-2 (COX-2) activity has been implicated in the pathogenesis of cerebral ischemia. To determine whether COX-2 activity within the neuron itself exacerbates hypoxic neuronal injury, neuron-enriched cultures were subjected to anoxia. Treatment with COX-2 selective antagonists decreased cell death. Neurons cultured from homozygous COX-2 gene disrupted mice were resistant to hypoxia compared to those of heterozygotes. Infection of primary neurons with AAV expressing COX-2 exacerbated cell death compared to neurons infected with enhanced green fluorescent protein (EGFP) control vector. Addition of PGE2, PGD2 or PGF2 alpha to the medium exacerbated injury, suggesting that the deleterious effects of COX-2 overexpression in hypoxia could be mediated by direct receptor mediated effects of prostaglandins. Overexpression of COX-2 did not increase expression of cyclin D1 or phosphoretinoblastoma protein (pRb), or cleavage of caspase 3 suggesting that this cell cycle mechanism does not mediate COX-2 toxicity in this model.
Li
Wenjin
W
Geriatric Research Educational and Clinical Center (00-GR-H), VA Pittsburgh Healthcare System, Highland Drive, Pittsburgh, PA 15205, USA.
Wu
Shasha
S
Hickey
Robert W
RW
Rose
Marie E
ME
Chen
Jun
J
Graham
Steven H
SH
D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000096:biosynthesis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D002534:Hypoxia, Brain / Q000201:enzymology* / Q000473:pathology*; D007150:Immunohistochemistry; D009474:Neurons / Q000201:enzymology* / Q000473:pathology*; D011247:Pregnancy; D015230:Prostaglandin D2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D052246:Cyclooxygenase 2 Inhibitors; D019938:Cyclin D1; D049452:Green Fluorescent Proteins; D015237:Dinoprost; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D015230:Prostaglandin D2