, Volume 39, Issue 4, pp 1594–1602 | Cite as

Inhibiting High-Mobility Group Box 1 (HMGB1) Attenuates Inflammatory Cytokine Expression and Neurological Deficit in Ischemic Brain Injury Following Cardiac Arrest in Rats

  • Mei Xu
  • Gui-ming Zhou
  • Li-hua Wang
  • Li Zhu
  • Jin-mei Liu
  • Xiao-dong Wang
  • Hong-tao Li
  • Lei Chen


Cardiac arrest (CA), if untreated for more than 5 min, can induce severe brain damage, the underlying mechanism of which is still unclear. Previous studies have indicated that high-mobility group box 1 (HMGB1), a nuclear protein implicated in several inflammatory disorders, is involved in the inflammatory processes following brain ischemia. However, the role of HMGB1 in brain dysfunction after CA is yet to be determined. In a rat CA model, HMGB1 protein expression was higher at 1, 3, and 7 days post-CA, compared to that in naïve and sham-treated rats. Following injection of HMGB1 antibody (anti-HMGB1) into the cerebral ventricles, neurological deficit scores were significantly decreased in the CA group as compared to that in the naïve and sham group. Nissl staining showed significant neuronal loss in the hippocampal CA1 region following CA, which was significantly attenuated by anti-HMGB1-treatment (10 and 50 μg) in comparison with the vehicle-injected control. CA induced a significant increase in the levels of the cytokine interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) in the hippocampus as revealed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Treatment with anti-HMGB1 significantly inhibited IL-1β and TNF-α expression. Our study suggests that HMGB1 contributes significantly to CA-induced brain dysfunction and that inhibiting HMGB1 function and expression may be an effective therapeutic approach to CA-induced ischemic brain injury.


cardiac arrest resuscitation high-mobility group box 1 hippocampus neurological deficit 



This work was supported by the Scientific Research Fund Project of Tianjin Health Bureau (303070100201), the Scientific Research Fund of Tianjin Medical University (3030502030070), and the National Key Clinical Specialty Project.


Conflict of Interest

The authors declare that there are no conflicts of interest.


  1. 1.
    Andersson, U., H. Erlandsson-Harris, H. Yang, and K.J. Tracey. 2002. HMGB1 as a DNA-binding cytokine. J Leukoc Biol. 72: 1084–1091.PubMedGoogle Scholar
  2. 2.
    Bottiger, B.W., B. Schmitz, C. Wiessner, P. Vogel, and K.A. Hossmann. 1998. Neuronal stress response and neuronal cell damage after cardiocirculatory arrest in rats. J Cereb Blood Flow Metab. 18: 1077–1087.CrossRefPubMedGoogle Scholar
  3. 3.
    Boutin, H., R.A. LeFeuvre, R. Horai, M. Asano, Y. Iwakura, and N.J. Rothwell. 2001. Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci. 21: 5528–5534.PubMedGoogle Scholar
  4. 4.
    Chakraborty, S., D.K. Kaushik, M. Gupta, and A. Basu. 2010. Inflammasome signaling at the heart of central nervous system pathology. J Neurosci Res. 88: 1615–1631.PubMedGoogle Scholar
  5. 5.
    Ding, H.S., J. Yang, F.L. Gong, J. Yang, J.W. Ding, S. Li, and Y.R. Jiang. 2012. High mobility group box 1 mediates neutrophil recruitment in myocardial ischemia-reperfusion injury through toll like receptor 4-related pathway. Gene. 509: 149–153.CrossRefPubMedGoogle Scholar
  6. 6.
    Eltzschig, H.K., and T. Eckle. 2011. Ischemia and reperfusion—from mechanism to translation. Nat Med. 17: 1391–1401.CrossRefPubMedGoogle Scholar
  7. 7.
    Gao, C.J., L. Niu, P.C. Ren, W. Wang, C. Zhu, Y.Q. Li, W. Chai, and X.D. Sun. 2012. Hypoxic preconditioning attenuates global cerebral ischemic injury following asphyxial cardiac arrest through regulation of delta opioid receptor system. Neuroscience. 202: 352–362.CrossRefPubMedGoogle Scholar
  8. 8.
    Kwon, W.Y., G.J. Suh, K.S. Kim, H.J. Lee, K.Y. Jeong, Y.H. Kwak, and K. Kim. 2013. Niacin suppresses the mitogen-activated protein kinase pathway and attenuates brain injury after cardiac arrest in rats. Crit Care Med. 41: e223–e232.CrossRefPubMedGoogle Scholar
  9. 9.
    Lotze, M.T., and K.J. Tracey. 2005. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 5: 331–342.CrossRefPubMedGoogle Scholar
  10. 10.
    Mitola, S., M. Belleri, C. Urbinati, D. Coltrini, B. Sparatore, M. Pedrazzi, E. Melloni, and M. Presta. 2006. Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol. 176: 12–15.CrossRefPubMedGoogle Scholar
  11. 11.
    Morancho, A., A. Rosell, L. Garcia-Bonilla, and J. Montaner. 2010. Metalloproteinase and stroke infarct size: role for anti-inflammatory treatment. Ann N Y Acad Sci. 1207: 123–133.CrossRefPubMedGoogle Scholar
  12. 12.
    Nichol, G., E. Thomas, C.W. Callaway, J. Hedges, J.L. Powell, T.P. Aufderheide, T. Rea, R. Lowe, T. Brown, J. Dreyer, D. Davis, A. Idris, and I. Stiell. 2008. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 300: 1423–1431.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Pedrazzi, M., M. Patrone, M. Passalacqua, E. Ranzato, D. Colamassaro, B. Sparatore, S. Pontremoli, and E. Melloni. 2007. Selective proinflammatory activation of astrocytes by high-mobility group box 1 protein signaling. J Immunol. 179: 8525–8532.CrossRefPubMedGoogle Scholar
  14. 14.
    Qiu, J., J. Xu, Y. Zheng, Y. Wei, X. Zhu, E.H. Lo, M.A. Moskowitz, and J.R. Sims. 2010. High-mobility group box 1 promotes metalloproteinase-9 upregulation through Toll-like receptor 4 after cerebral ischemia. Stroke. 41: 2077–2082.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Shichita, T., R. Sakaguchi, M. Suzuki, and A. Yoshimura. 2012. Post-ischemic inflammation in the brain. Front Immunol. 3: 132.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wang, Q., Q. Ding, Y. Zhou, X. Gou, L. Hou, S. Chen, Z. Zhu, and L. Xiong. 2009. Ethyl pyruvate attenuates spinal cord ischemic injury with a wide therapeutic window through inhibiting high-mobility group box 1 release in rabbits. Anesthesiology. 110: 1279–1286.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang, Y., Y. Li, L. Wang, Y. Kang, J. Zhang, Z. Liu, K. Wang, A. Kaye, and L. Chen. 2015. Tanshinone IIA attenuates chronic pancreatitis-induced pain in rats via downregulation of HMGB1 and TRL4 expression in the spinal cord. Pain Physician 18: E615–E628.PubMedGoogle Scholar
  18. 18.
    Yanai, H., T. Ban, and T. Taniguchi. 2012. High-mobility group box family of proteins: ligand and sensor for innate immunity. Trends Immunol. 33: 633–640.CrossRefPubMedGoogle Scholar
  19. 19.
    Yanai, H., T. Ban, Z. Wang, M.K. Choi, T. Kawamura, H. Negishi, M. Nakasato, Y. Lu, S. Hangai, R. Koshiba, D. Savitsky, L. Ronfani, S. Akira, M.E. Bianchi, K. Honda, T. Tamura, T. Kodama, and T. Taniguchi. 2009. HMGB proteins function as universal sentinels for rnucleic-acid-mediated innate immune responses. Nature. 462: 99–103.Google Scholar
  20. 20.
    Zhang, J., H.K. Takahashi, K. Liu, H. Wake, R. Liu, T. Maruo, I. Date, T. Yoshino, A. Ohtsuka, S. Mori, and M. Nishibori. 2011. Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats. Stroke. 42: 1420–1428.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Mei Xu
    • 1
  • Gui-ming Zhou
    • 2
  • Li-hua Wang
    • 3
  • Li Zhu
    • 2
  • Jin-mei Liu
    • 2
  • Xiao-dong Wang
    • 4
  • Hong-tao Li
    • 4
  • Lei Chen
    • 5
  1. 1.Department of PediatricsTianjin Medical University General HospitalTianjinChina
  2. 2.Department of UltrasoundTianjin Medical University General HospitalTianjinChina
  3. 3.Department of Cardiothoracic SurgeryTianjin Medical University General HospitalTianjinChina
  4. 4.Department of EndocrinologyTianjin Corps Hospital of Chinese People’s Armed Police ForcesTianjinChina
  5. 5.Department of UltrasoundTianjin Corps Hospital of Chinese People’s Armed Police ForcesTianjinChina

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