Cyclooxygenase-2-dependent neuronal death proceeds via superoxide anion generation

Joo Young Im, Doyeun Kim, Sang Gi Paik, Pyung Lim Han

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Cyclooxygenase-2 (COX-2) expression is induced in the neurons of the pathologic brain and elevated COX-2 expressions can lead to neuronal death. Here, we report that COX-2 induction in cortical neurons induced by LPS pretreatment for more than 12 h increased the neurotoxic effects of low doses of Fe2+ by more than 2.5-fold. Moreover, the neurotoxicity induced by 30 μM Fe2+ in LPS-pretreated cells exceeded that induced by 100 μM Fe2+ in LPS-untreated cells. LPS pretreatment also similarly aggravated the neurotoxic effects of low doses of H2O2, Zn2+, and sodium nitroprusside. This LPS-induced Fe2+-toxicity enhancement was blocked by trolox, vitamin C, the SOD mimetic MnTBAP, and by the COX-2-specific inhibitor NS398, but not by inhibitors of xanthine oxidase, NADPH oxidase, NOS, and monoamine oxidase. Cortical neurons with enhanced COX-2 expression showed superoxide generation, GSH depletion, and lipid peroxidation in response to low doses of Fe2+, and all of these changes were repressed by MnTBAP or NS398. Consistent with this pharmacological data, cortical neurons prepared from COX-2 knockout mice showed marked reductions in LPS-induced Fe2+-toxicity enhancement and superoxide generation. These results suggest that COX-2 functions as a cellular factor which induces superoxide-mediated cell death in primary cortical neurons.

Original languageEnglish
Pages (from-to)960-972
Number of pages13
JournalFree Radical Biology and Medicine
Volume41
Issue number6
DOIs
StatePublished - 15 Sep 2006

Keywords

  • COX-2
  • MnTBAP
  • Neuronal death
  • NS398
  • SOD
  • Superoxide

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