Skip to main content

Ghrelin Inhibits High Glucose-Induced PC12 Cell Apoptosis by Regulating TLR4/NF-κB Pathway


Ghrelin has a protective effect on diabetic encephalopathy. To expound the protective mechanism, we investigated the effects of ghrelin on high glucose-induced cell apoptosis and intracellular signaling in cultured PC12, which is a suitable model for studying neuronal cell death. High glucose-induced PC12 apoptosis was significantly inhibited by co-treatment of ghrelin. Sustaining inflammatory response is one of the molecular mechanisms of diabetic encephalopathy and TLR4 signaling has close relationship with inflammatory response. But there is no report about the biologic role of toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) signaling in controlling high glucose-induced PC12 apoptosis by ghrelin. In this study, we found that TLR4/NF-κB pathway was activated by high glucose stimulation in PC12 and significantly alleviated by the co-treatment of ghrelin. From these findings, we made the conclusion that ghrelin could attenuate the symptoms of diabetic encephalopathy, which alleviates inflammatory reaction of diabetic encephalopathy by regulating TLR4/NF-κB pathway.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5



Toll-like receptor 4/nuclear factor-κB


High glucose


Transmission electron microscopy


Fetal bovine serum


Dulbecco’s modified Eagle’s medium


Dimethyl sulfoxide




Sodium dodecyl sulfate




American Type Culture Collection


Phosphate-buffered saline


Myeloid differentiation primary response gene 88


Human tumor necrosis factor receptor-associated factor 6


  1. 1.

    Biessels, G.J., I.J. Deary, and C.M. Ryan. 2008. Cognition and diabetes: a life span perspective. Lancet Neurology 7: 184–190.

    PubMed  Article  Google Scholar 

  2. 2.

    Ferguson, S.C., A. Blane, J. Wardlaw, et al. 2005. Influence of early onset age of type 1 diabetes on cerebral structure and cognitive function. Diabetes Care 28: 1431–1437.

    PubMed  Article  Google Scholar 

  3. 3.

    Perantie, D.C., J. Wu, J.M. Koller, et al. 2007. Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth with type 1 diabetes. Diabetes Care 30: 2331–2337.

    PubMed  Article  Google Scholar 

  4. 4.

    Hoffman, W.H., C.M. Artlett, W. Zhang, et al. 2008. Receptor for advanced glycation end products and neuronal deficit in fatal brain edema of diabetic ketoacidosis. Brain Research 1238: 154–162.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Francis, G.J., J.A. Martinez, W.Q. Liu, et al. 2008. Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type 1 diabetic encephalopathy. Brain 131(Pt 12): 3311–3334.

    PubMed  Article  Google Scholar 

  6. 6.

    Wu, R., M. Zhou, P. Das, et al. 2007. Ghrelin inhibits sympathetic nervous activity in sepsis. American Journal of Physiology. Endocrinology and Metabolism 293: E1697–E1702.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Wu, R., W. Dong, M. Zhou, et al. 2007. Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats. American Journal of Respiratory and Critical Care Medicine 176: 805–813.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Cowley, M.A., R.G. Smith, S. Diano, et al. 2003. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37: 649–661.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Lin, Y., K. Matsumura, M. Fukuhara, et al. 2004. Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats. Hypertension 43: 977–982.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Zhang, W., T.R. Lin, Y. Hu, et al. 2004. Ghrelin stimulates neurogenesis in the dorsal motor nucleus of the vagus. The Journal of Physiology 559: 729–737.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Navarro-González, J.F., and C. Mora-Fernández. 2008. The role of inflammatory cytokines in diabetic nephropathy. Journal of the American Society of Nephrology 19: 433–442.

    PubMed  Article  Google Scholar 

  12. 12.

    Teng, W., L. Wang, W. Xue, and C. Guan. 2009. Activation of TLR4-mediated NFkappaB signaling in hemorrhagic brain in rats. Mediators of Inflammation 2009: 473276.

    PubMed  Article  Google Scholar 

  13. 13.

    Martin, T.F., and R.N. Grishanin. 2003. PC12 cells as a model for studies of regulated secretion in neuronal and endocrine cells. Methods in Cell Biology 71: 267–286.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Abid-Essefi, S., I. Baudrimont, W. Hassen, et al. 2003. DNA fragmentation, apoptosis and cell cycle arrest induced by zearalenone in cultured DOK, Vero and Caco-2 cells: prevention by vitamin E. Toxicology 192: 237–248.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Pickup, J.C. 2004. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27(3): 813–823.

    PubMed  Article  Google Scholar 

  16. 16.

    Spranger, J., A. Kroke, M. Mohlig, et al. 2003. Inflammatory cytokines and the risk to develop type2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. Diabetes 52: 812–817.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Thorand, B., H. Lowel, A. Schneider, et al. 2003. C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study. Archives of Internal Medicine 163: 93–99.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Lontchi-Yimagou, Eric, et al. 2013. Diabetes mellitus and inflammation. Current Diabetes Reports 13(3): 435–444.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Kempf, Kerstin, et al. 2006. Inflammation in metabolic syndrome and type 2 diabetes impact of dietary glucose. Annals of the New York Academy of Sciences 1084: 30–48.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Sima, Anders A.F., Weixian Zhang, Christian W. Kreipke, et al. 2009. Inflammation in diabetic encephalopathy is prevented by C-peptide. Rev Diabet Stud 6(1): 37–42.

  21. 21.

    Sharifi, Ali M., Seyed Hadi Mousavi, and Mona Farhadi. 2007. Study of high glucose-induced apoptosis in PC12 cells: role of Bax protein. J Pharmacol Sci 104: 258–262.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Miao, Y., Q. Xia, Z. Hou, et al. 2007. Ghrelin protects cortical neuron against focal ischemia/reperfusion in rats. Biochemical and Biophysical Research Communications 359: 795–800.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Ma, Louyan, Dongmin Zhang, Yong Tang, et al. 2011. Ghrelin-attenuated cognitive dysfunction in streptozotocin-induced diabetic rats. Alzheimer Disease and Associated Disorders 25: 352–363.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Dolgor, B., P. Kalpesh, and D.T. Dennis. 2011. The effects of ghrelin on inflammation and the immune system. Molecular and Cellular Endocrinology 340: 44–58.

    Article  Google Scholar 

  25. 25.

    Madison, L.D., J.M. Scarlett, P. Levasseur, et al. 2008. Prostacyclin signaling regulates circulating ghrelin during acute inflammation. Journal of Endocrinology 196: 263–273.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Dixit, V.D., et al. 2009. Reduction of T cell-derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation. Blood 113(21): 5202–5205.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Wei, G.L., et al. 2004. Ghrelin inhibits proinflammatory responses and nuclear factor-κB activation in human endothelial cells. Circulation 109: 2221–2226.

    Article  Google Scholar 

  28. 28.

    Cletus, C., et al. 2011. Ghrelin suppresses inflammation and neuronal nitric oxide synthase in focal cerebral ischemia via the vagus nerve. Shock 35(3): 258–265.

    Article  Google Scholar 

  29. 29.

    Talat, W., et al. 2008. Exogenous ghrelin modulates release of pro- and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways. Surgery 143(3): 334–342.

    Article  Google Scholar 

  30. 30.

    Downes, C.E., and P.J. Crack. 2010. Neural injury following stroke: are Toll-like receptors the link between the immune system and the CNS. British Journal of Pharmacology 160: 1872–1888.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Racke, M.K., and P.D. Drew. 2009. Toll-like receptors in multiple sclerosis. Current Topics in Microbiology and Immunology 336: 155–168.

    PubMed  Article  CAS  Google Scholar 

Download references


Our work was supported by grants from both the Key Projects of Medical Science sponsored by Chongqing Municipal Health Bureau in the People’s Republic of China (2010-1-8) and the Natural Science Foundation of Chongqing in the People’s Republic of China (CSTC, 2010BB5396). The study is also supported by the National Foundation of Natural Science of China (no. 81170752).

Conflict of interest

The authors declare no competing interests.

Author information



Corresponding author

Correspondence to Qian Xiao.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, X., Xiao, Q., Zhao, K. et al. Ghrelin Inhibits High Glucose-Induced PC12 Cell Apoptosis by Regulating TLR4/NF-κB Pathway. Inflammation 36, 1286–1294 (2013).

Download citation


  • PC12
  • ghrelin
  • high glucose
  • TLR4/NF-κB pathway
  • inflammation