Nox4-dependent H2O2 production contributes to chronic glutamate toxicity in primary cortical neurons

Jong Seong Ha, Jeong Eun Lee, Jae Ran Lee, Chul Sang Lee, Jin Soo Maeng, Yun Soo Bae, Ki Sun Kwon, Sung Sup Park

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35 Scopus citations


Reactive oxygen species (ROS) can trigger neuronal cell death and has been implicated in a variety of neurodegenerative diseases as well as brain ischemia. Here, we demonstrate that chronic (but not acute) glutamate toxicity in primary cortical neuronal cultures is associated with hydrogen peroxide (H2O2) accumulation in the culture medium and that neurotoxicity can be eliminated by external catalase treatment. Neuronal cultures in Ca2+-free medium or treated with BAPTA showed reduced glutamate-induced H2O2 generation, indicating that H2O2 generation is Ca2+-dependent. Pharmacological and genetic approaches revealed that NADPH oxidase plays a role in glutamate-induced H2O2 generation and that activation of NMDA and AMPA receptors is involved in this H2O2 generation. The Nox4 siRNA reduced NMDA-induced H2O2 production by 54% and cytotoxicity in parallel, suggesting that Nox4-containing NADPH oxidase functions NMDA receptor-mediated H2O2 production resulting in neurotoxicity. These findings suggest that the modulation of NADPH oxidase can be used as a new therapeutic strategy for glutamate-induced neuronal diseases.

Original languageEnglish
Pages (from-to)1651-1661
Number of pages11
JournalExperimental Cell Research
Issue number10
StatePublished - Jun 2010

Bibliographical note

Funding Information:
We thank Pyung-Lim Han, Uk Namgung, Chae Young Hwang for valuable comments and discussion. This work was supported by the grants from Korea Research Council of Fundamental Science and Technology and National Research Foundation ( M10642040003 and M10503010002 to K.-S. K.) and by the Converging Research Center Program funded by the Ministry of Education, Science and Technology (2009-0082237).


  • Chronic exposure
  • Glutamate toxicity
  • Nox4
  • Reactive oxygen species


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