Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia.
Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia.
复制标题
白介素-6介导精神分裂症的氯胺酮模型中NADPH-氧化酶的增加。
DOI：
10.1523/jneurosci.4457-08.2008
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发表时间：
2008-12-17
期刊：
影响因子：
--
通讯作者：
Dugan LL
中科院分区：
文献类型：
--
作者：
Behrens MM;Ali SS;Dugan LL
成人暴露于NMDA受体拮抗剂，如氯胺酮，可导致人类精神病，并加重精神分裂症患者的症状。我们最近发现氯胺酮激活脑内先天免疫酶nadph氧化酶，产生的超氧化物导致表达钙结合蛋白小白蛋白（PV）的快速尖峰抑制性中间神经元亚群功能障碍。在这里，我们表明神经元产生白细胞介素-6 （IL-6）是必要的和充分的氯胺酮介导的nadph氧化酶在大脑中的激活。通过抗IL-6阻断抗体或IL-6缺陷小鼠体内去除神经元培养物中的IL-6，可以阻止氯胺酮引起的超氧化物增加，并挽救中间神经元。越来越多的证据表明，精神分裂症患者的抗氧化防御能力下降，最近的一项临床试验表明，增强这些防御能力可能会改善这种疾病的症状。我们的研究结果表明，氯胺酮诱导的IL-6负责脑内nadph氧化酶的激活，这表明降低脑内这种细胞因子的水平可能保护快速峰值pv -中间神经元的gaba能表型，从而减弱氯胺酮的促精神病作用。
Adult exposure to NMDA receptor antagonists, such as ketamine, produces psychosis in humans, and exacerbates symptoms in schizophrenic patients. We recently showed that ketamine activates the innate immune enzyme NADPH-oxidase in brain, and that the superoxide produced leads to dysfunction of a subset of fast-spiking inhibitory interneurons expressing the calcium-binding protein parvalbumin (PV). Here we show that neuronal production of interleukin-6 (IL-6) is necessary and sufficient for ketamine-mediated activation of NADPH-oxidase in brain. Removal of IL-6 in neuronal cultures by anti-IL-6 blocking antibodies, or in vivo by use of IL-6-deficient mice, prevented the increase in superoxide by ketamine and rescued the interneurons. Accumulating evidence suggests that schizophrenia patients suffer from diminished antioxidant defenses, and a recent clinical trial showed that enhancing these defenses may ameliorate symptoms of the disease. Our results showing that ketamine-induced IL-6 is responsible for the activation of NADPH-oxidase in brain suggest that reducing brain levels of this cytokine may protect the GABAergic phenotype of fast-spiking PV-interneurons and thus attenuate the propsychotic effects of ketamine.