Cyclooxygenase-2 inhibitor NS-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity

Eiichi Araki, Colleen Forster, Janet M. Dubinsky, M. Elizabeth Ross, Costantino Iadecola

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

Background and Purpose - 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/μ/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 E2 (PGE2) and of the cytokine tumor necrosis factor-α (TNF-α). NS-398 (10μmol/L) blocked the PGE2 increase, attenuated the TNF-α increase, and prevented the neuronal death produced by LPS. TNF-α-blocking antibodies attenuated LPS-induced neuronal death, but the protection was less pronounced than that afforded by NS-398. LPS failed to elevate PGE2 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-α-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.

Original languageEnglish (US)
Pages (from-to)2370-2375
Number of pages6
JournalStroke
Volume32
Issue number10
DOIs
StatePublished - 2001

Keywords

  • Cerebral ischemia
  • Cytokines
  • Inflammation
  • Lipopolysaccharides
  • Mice
  • Neurons

Fingerprint Dive into the research topics of 'Cyclooxygenase-2 inhibitor NS-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity'. Together they form a unique fingerprint.

  • Cite this