Nox4-dependent H2O2 production contributes to chronic glutamate toxicity in primary cortical neurons |
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Authors: | Jong Seong Ha Jae-Ran Lee Jin-Soo Maeng Ki-Sun Kwon Sung Sup Park |
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Affiliation: | a Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 111 Gwahangno, Yuseong, Daejeon 305-806, Korea b Brain Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong, Daejeon 305-806, Korea c Department of Biological Science, Kunsan National University, Gunsan, Jeollabuk-do 573-701, Korea d Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul 120-750, Korea |
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Abstract: | 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. |
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Keywords: | AMPA, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione DHPG, (S)-3,5-dihydroxyphenylglycine DPI, diphenyleneiodonium H2O2, hydrogen peroxide KRPG, Krebs-Ringer phosphate buffer LDH, lactate dehydrogenase MK801, methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine PBS, phosphate-buffered saline ROS, reactive oxygen species siRNA, small interfering RNAs SOD1, superoxide dismutase 1 iGluR, ionotropic glutamate receptor |
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