title: Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity.
abstract: OBJECTIVE
  The prostanoid-synthesizing enzyme cyclooxygenase (COX)-2 is markedly upregulated after cerebral ischemia and may participate in the mechanisms by which postischemic inflammation contributes to the late stages of ischemic brain injury. In the present study, we sought to provide additional evidence for a role of COX-2 in the mechanisms of neurotoxicity associated with inflammation.
  
  
  METHODS
  Nine-day-old neuronal-glial cultures, prepared from the cerebral cortex of newborn C57BL/6J mice, were exposed to lipopolysaccharide (LPS), a potent proinflammatory agent. The contribution of COX-2 was investigated by using the COX-2 inhibitor NS-398.
  
  
  RESULTS
  LPS produced a dose-dependent (0.001 to 10 microg/mL) and selective neuronal death that was well developed 72 hours after treatment. The effect was associated with a marked increase in the concentration of the COX reaction product prostaglandin E(2) (PGE(2)) and of the cytokine tumor necrosis factor-alpha (TNF-alpha). NS-398 (10 micromol/L) blocked the PGE(2) increase, attenuated the TNF-alpha increase, and prevented the neuronal death produced by LPS. TNF-alpha-blocking antibodies attenuated LPS-induced neuronal death, but the protection was less pronounced than that afforded by NS-398. LPS failed to elevate PGE(2) or to produce cell death in neuron-enriched cultures, suggesting that glial cells are required for these effects.
  
  
  CONCLUSIONS
  COX-2, in part through TNF-alpha-related mechanisms, contributes to LPS-induced neuronal death. The data support the hypothesis that COX-2, in addition to its role in glutamate excitotoxicity, participates in the cytotoxicity associated with inflammation.
authors.affiliation: Center for Clinical and Molecular Neurobiology, Department of Neurology, University of Minnesota, Minneapolis 55455, USA.
authors.forename: E
authors.initials: E
authors.lastname: Araki
authors.forename: C
authors.initials: C
authors.lastname: Forster
authors.forename: J M
authors.initials: JM
authors.lastname: Dubinsky
authors.forename: M E
authors.initials: ME
authors.lastname: Ross
authors.forename: C
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation / Q000096:biosynthesis; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D007770:L-Lactate Dehydrogenase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone