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Inhibition of the Receptor for Advanced Glycation End-Products (RAGE) Attenuates Neuroinflammation While Sensitizing Cortical Neurons Towards Death in Experimental Subarachnoid Hemorrhage

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Abstract

Subarachnoid hemorrhage (SAH) is a threatening and devastating neurological insult with high mortality and morbidity rates. Despite considerable efforts, the underlying pathophysiological mechanisms are still poorly understood. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that has been implicated in various pathological conditions. We previously showed that RAGE was upregulated and may be involved in pathophysiology of SAH. In the current study, we investigated its potential role in SAH. We found that the upregulation of RAGE after SAH was NF-κB-dependent positive feedback regulation. Further, pharmacological inhibition of RAGE attenuated neuroinflammation, indicating a possible contributive role of RAGE in inflammation-associated brain injury after SAH. Conversely, however, inhibition of RAGE sensitized neurons, exacerbating cell death, which correlated with augmented apoptosis and diminished autophagy, suggesting that activation of RAGE may protect against SAH-induced neuronal injury. Furthermore, we demonstrate that inhibition of RAGE significantly reduced brain edema and improved neurological function at day 1 but not at day 3 post-SAH. Taken together, these results suggest that RAGE exerts dual role after SAH. Our findings also suggest caution should be exercised in setting RAGE-targeted treatment for SAH.

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Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No. 81371294) and the Natural Science Foundation of Jiangsu Province (No. BK20141375).

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Authors and Affiliations

  1. Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China

    Hua Li, Jia-Sheng Yu, Ru-Dong Chen & Hong-Kuan Yang

  2. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu Province, China

    Hua Li, Ding-Ding Zhang, Yi-Qing Yang, Zhuang Yu & Chun-Hua Hang

  3. Department of Neurosurgery, Jinling Hospital, School of Medicine, Southern Medical University (Guangzhou), Nanjing, Jiangsu Province, China

    Li-Tian Huang & Chun-Hua Hang

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  1. Hua Li
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Li, H., Yu, JS., Zhang, DD. et al. Inhibition of the Receptor for Advanced Glycation End-Products (RAGE) Attenuates Neuroinflammation While Sensitizing Cortical Neurons Towards Death in Experimental Subarachnoid Hemorrhage. Mol Neurobiol 54, 755–767 (2017). https://doi.org/10.1007/s12035-016-9703-y

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