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Etanercept Alleviates Early Brain Injury Following Experimental Subarachnoid Hemorrhage and the Possible Role of Tumor Necrosis Factor-α and c-Jun N-Terminal Kinase Pathway

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Abstract

Cerebral inflammation plays a crucial role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study investigated the effects of c-Jun N-terminal kinase (JNK) inhibitor SP600125, acetylcholine (Ach), etanercept, and anti-TNF-α on cellular apoptosis in the cerebral cortex and the hippocampus, in order to establish the role of JNK and TNF-α in EBI. The SAH model was established using an endovascular puncture protocol. The reliability of the EBI model was determined by phosphorylated-Bad (pBad) immunohistochemistry. Neurological scores were recorded and western blot was used to detect the expression of JNK and TNF-α, and TUNEL assay was used to mark apoptotic cells. The results showed that pBad positive cells were evenly distributed in the cerebral cortex at different time points. The highest expression of pBad was reached 1 day after SAH, and pJNK and TNF-α reached their peak expression at 2 days after SAH. SP600125, Ach, and etanercept significantly decreased the level of pJNK and TNF-α in the cerebral cortex and the hippocampus. In addition, SP600125 and etanercept reduced cellular apoptosis in the cerebral cortex and the hippocampus and significantly improved neurological scores at 2 days after SAH potentially via inhibition of the JNK-TNF-α pathway. Ach reduced cellular apoptosis only in the cerebral cortex. It is possible that JNK induces TNF-α expression, which in turn enhances JNK expression in EBI after SAH, leading to increased apoptosis in the cerebral cortex and the hippocampus. Thus, our results indicate that that etanercept may be a potential therapeutic agent to alleviate EBI.

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Acknowledgments

This research was supported by the National Natural Science Foundation of China (No. 30870844), the Key Scientific and Technological Innovation Special Projects of Shaanxi “13115” (No. 2008ZDKG-66) and the Special Research Fund for the Doctoral Disciplinary Points in Universities of Ministry of Education (No. 20110201110060).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Neurosurgery, the First Affiliated Hospital, Medical School of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an, Shaanxi Province, 710061, People’s Republic of China

    Bin-fei Zhang, Jin-ning Song, Xu-dong Ma, Yong-lin Zhao, Zun-wei Liu, Yu Li, Peng Sun, Dan-dong Li, Hong-gang Pang & Ting-qin Huang

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  1. Bin-fei Zhang
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Correspondence to Jin-ning Song.

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Bin-fei Zhang and Jin-ning Song should be listed as the co-first authors.

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Zhang, Bf., Song, Jn., Ma, Xd. et al. Etanercept Alleviates Early Brain Injury Following Experimental Subarachnoid Hemorrhage and the Possible Role of Tumor Necrosis Factor-α and c-Jun N-Terminal Kinase Pathway. Neurochem Res 40, 591–599 (2015). https://doi.org/10.1007/s11064-014-1506-9

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