Nox4-dependent H2O2 production contributes to chronic glutamate toxicity in primary cortical neurons
Nox4-dependent H2O2 production contributes to chronic glutamate toxicity in primary cortical neurons
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DOI：
10.1016/j.yexcr.2010.03.021
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发表时间：
2010-06-10
影响因子：
3.7
通讯作者：
Park, Sung Sup
中科院分区：
文献类型：
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作者：
Ha, Jong Seong;Lee, Jeong Eun;Park, Sung Sup
活性氧（ROS）可以引发神经元细胞死亡，并与多种神经退行性疾病和脑缺血有关。在这里，我们证明了原发性皮质神经元培养中的慢性（但不是急性）谷氨酸毒性与培养基中过氧化氢（H2O2）的积累有关，并且神经毒性可以通过外部过氧化氢酶治疗消除。在无Ca2+培养基或BAPTA处理的神经元培养中，谷氨酸诱导的H2O2生成减少，表明H2O2生成依赖于Ca2+。药理学和遗传学方法表明，NADPH氧化酶在谷氨酸诱导的H2O2生成中起作用，NMDA和AMPA受体的激活参与了H2O2的生成。Nox4 siRNA将NMDA诱导的H2O2产生降低54%，并同时降低细胞毒性，这表明含有NADPH氧化酶的Nox4发挥了NMDA受体介导的H2O2产生的功能，从而导致神经毒性。这些发现提示，调节NADPH氧化酶可作为谷氨酸诱导的神经元疾病的一种新的治疗策略。(c) 2010爱思唯尔公司版权所有。
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. (c) 2010 Elsevier Inc. All rights reserved.