Neuronal Cyclooxygenase-2 Activity and Prostaglandins PGE2, PGD2, and PGF2α Exacerbate Hypoxic Neuronal Injury in Neuron-enriched Primary Culture |
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Authors: | Wenjin Li Shasha Wu Robert W Hickey Marie E Rose Jun Chen Steven H Graham |
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Institution: | (1) Geriatric Research Educational and Clinical Center (00-GR-H), V.A. Pittsburgh Healthcare System, Highland Drive, Pittsburgh, PA 15205, USA;(2) Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;(3) Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;(4) Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA |
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Abstract: | 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 PGF2α 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. |
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Keywords: | Cyclooxygenase Hypoxia Prostaglandins Primary neuronal culture Cyclin D1 Retinoblastoma protein |
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