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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >NF-κB-dependent and -independent pathways in the protective effects of activated protein C in hippocampal and cortical neurons at excitotoxicity
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NF-κB-dependent and -independent pathways in the protective effects of activated protein C in hippocampal and cortical neurons at excitotoxicity

机译：NF-κB依赖性和非依赖性通路对活化蛋白C对海马和皮层神经元兴奋性毒性的保护作用

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摘要

The transcription factor NF-κB regulates the expression of multiple genes involved in inflammation, apoptotic cell death and cell survival. We previously demonstrated that activated protein C (APC), a serine protease of hemostasis with anticoagulant activity, protected cultured rat cortical and hippocampal neurons against glutamate-induced excitotoxicity, a model of ischemic stroke. We reported that APC suppressed the translocation of NF-κBp65/RelA into the nucleus of neurons. However, it is not known whether APC-induced protection of neurons against cell death occurs via regulation of NF-κB activation or NF-κB-independent p53 expression. It is also unclear whether cleaved caspase-3 and caspase-independent AIF and Bax/Bcl-2 expression are involved at excitotoxicity. To elucidate the NF-κB dependent and -independent mechanisms in the APC-mediated cell survival, we analyzed in cortical and hippocampal neurons the effects of helenalin, a specific inhibitor of NF-κB activity, and APC on neuronal cell death and on the level of nuclear AIF, p53, caspase-3 and the apoptotic index (Bax/Bcl-2 ratio). We could demonstrate that helenalin (5. μM), like APC (1. nM), protects cultured neurons from glutamate-induced excitotoxicity. Both APC and helenalin inhibit AIF release from mitochondria and its translocation into the nucleus. They decrease the apoptotic index in neurons at excitotoxicity. However, APC, but not helenalin, reduced the glutamate-induced activation of caspase-3. Incubation of neurons with APC blocked the glutamate-induced increase in the nuclear level of p53 via NF-κB-independent pathway. Our findings demonstrate that, in the protective effect of APC in neurons at excitotoxicity, the NF-κB pathway is an important, but not the only pathway, and is significantly connected with neuronal survival at excitotoxicity.
机译：转录因子NF-κB调节与炎症，凋亡细胞死亡和细胞存活有关的多个基因的表达。我们先前证明，活化蛋白C（APC）是一种具有抗凝活性的止血丝氨酸蛋白酶，可保护培养的大鼠皮质和海马神经元免受谷氨酸诱导的兴奋性毒性（一种缺血性中风的模型）。我们报道了APC抑制NF-κBp65/ RelA易位到神经元核中。然而，尚不清楚APC诱导的神经元针对细胞死亡的保护作用是否通过调节NF-κB激活或独立于NF-κB的p53表达而发生。尚不清楚裂解的caspase-3和不依赖caspase的AIF和Bax / Bcl-2表达是否与兴奋性毒性有关。为了阐明APC介导的细胞存活中的NF-κB依赖性和非依赖性机制，我们在皮层和海马神经元中分析了海蓝蛋白（一种特定的NF-κB活性抑制剂）和APC对神经元细胞死亡和水平的影响。核AIF，p53，caspase-3和凋亡指数（Bax / Bcl-2比）的变化。我们可以证明，Helenalin（5.μM）和APC（1. nM）一样，可以保护培养的神经元免受谷氨酸诱导的兴奋性毒性作用。 APC和Helenalin均抑制线粒体中的AIF释放及其向核内的转运。它们在兴奋性毒性时降低神经元的凋亡指数。但是，APC而不是海蓝素可以降低谷氨酸诱导的caspase-3活化。用APC孵育神经元可通过非NF-κB依赖性途径阻止谷氨酸诱导的p53核水平升高。我们的发现表明，在APC对兴奋性神经元的保护作用中，NF-κB通路是重要的但不是唯一的途径，并且与兴奋性中毒的神经元存活密切相关。

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