NF-¦ÊB-dependent and -independent pathways in the protective effects of activated protein C in hippocampal and cortical neurons at excitotoxicity

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• 作者：Lubov Gorbacheva ; Svetlana Strukova ; Vsevolod Pinelis ; Shin¡¯ichi Ishiwata ; Rolf Stricker ; Georg Reiser
• 关键词：APC ; activated protein C ; EPCR ; endothelial protein C receptor ; PAR-1 ; protease-activated receptor-1 ; NF-¦ÊB ; nuclear factor kappa B ; AIF ; apoptosis-inducing factor ; p53 ; tumor suppressor protein p53
• 刊名：Neurochemistry International
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：63
• 期：2
• 页码：101-111
• 全文大小：2002 K

文摘

The transcription factor NF-¦ÊB 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-¦ÊBp65/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-¦ÊB activation or NF-¦ÊB-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-¦ÊB 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-¦ÊB 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 ¦ÌM), 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-¦ÊB-independent pathway. Our findings demonstrate that, in the protective effect of APC in neurons at excitotoxicity, the NF-¦ÊB pathway is an important, but not the only pathway, and is significantly connected with neuronal survival at excitotoxicity.