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Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α

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Abstract

It has been reported that activation of NF-κB is involved in excitotoxicity; however, it is not fully understood how NF-κB contributes to excitotoxicity. The aim of this study is to investigate if NF-κB contributes to quinolinic acid (QA)-mediated excitotoxicity through activation of microglia. In the cultured primary cortical neurons and microglia BV-2 cells, the effects of QA on cell survival, NF-κB expression and cytokines production were investigated. The effects of BV-2-conditioned medium (BCM) on primary cortical neurons were examined. The effects of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, and minocycline (MC), an inhibitor of microglia activation, on QA-induced excitotoxicity were assessed. QA-induced NF-κB activation and TNF-α secretion, and the roles of TNF-α in excitotoxicity were studied. QA at the concentration below 1 mM had no apparent toxic effects on cultured primary neurons or BV-2 cells. However, addition of QA-primed BCM to primary neurons did aggravate QA-induced excitotoxicity. The exacerbation of QA-induced excitotoxicity by BCM was partially ameliorated by inhibiting NF-κB and microglia activation. QA induced activation of NF-κB and upregulation of TNF-α in BV-2 cells. Addition of recombinant TNF-α mimicked QA-induced excitotoxic effects on neurons, and neutralizing TNF-α with specific antibodies partially abolished exacerbation of QA-induced excitotoxicity by BCM. These studies suggested that QA activated microglia and upregulated TNF-α through NF-κB pathway in microglia. The microglia-mediated inflammatory pathway contributed, at least in part, to QA-induced excitotoxicity.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81671252; 81000547; 30930035), the National key basic science project 973 project (No. 2011CB510003) and by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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    1. Department of Pharmacology and Laboratory of Aging and Nervous Diseases (SZS0703), College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China

      Wei Feng, Yan Wang, Zi-Qi Liu, Xuan Zhang, Rong Han, You-Zhu Miao & Zheng-Hong Qin

    2. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA

      Xuan Zhang

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    Wei Feng and Yan Wang contributed to this work equally.

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    Feng, W., Wang, Y., Liu, ZQ. et al. Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α. Apoptosis 22, 696–709 (2017). https://doi.org/10.1007/s10495-017-1363-5

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