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Trans-Resveratrol Attenuates High Fatty Acid-Induced P2X7 Receptor Expression and IL-6 Release in PC12 Cells: Possible Role of P38 MAPK Pathway

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ABSTRACT

Diabetic neuropathy (DNP) is the most common chronic complication of diabetes. Elevated free fatty acids (FFAs) have been recently recognized as major causes of inflammation and are relevant to the functional changes of nerve system in diabetes. Trans-resveratrol (RESV), a polyphenolic natural compound, has long been acknowledged to have anti-inflammation properties and may exert a neuroprotective effect on neuronal damage in diabetes, while the mechanisms underlying are largely unknown. Our previous study on differential PC12 cells cultured with high FFAs has shown chronic FFAs overload increased PC12 interleukin (IL)-6 release mediated by P2X7 receptor, a ligand-gated cation channel activated by extracellular adenosine triphosphate (ATP); a high FFA-induced activation of P38 mitogen-activated protein kinase (MAPK) pathway was pointed to be a potential underlying mechanism. Data from this study indicated that RESV, in a dose-dependent manner, reduced high FFA-induced IL-6 release by impeding the activation of P2X7 receptor, as shown by the results that both high FFA-elevated P2X7 receptor messenger RNA (mRNA) and protein expression as well as high FFA-evoked [Ca2+]i in response to 3′-O-(4-benzoyl) benzoyl-ATP (a selective P2X7 receptor agonist) were significantly attenuated. Meanwhile, high FFA-induced activation of P38 MAPK, an essential prerequisite for high FFA-activated P2X7 receptor and subsequent IL-6 release, was also dose-dependently abrogated by RESV. Furthermore, RESV may hamper the activation of P38a MAPK (one paramount P38 isoform) via forming hydrogen bonding with Thr175 residue, surrounding the two residues (Thy180 and Tyr182) essential for canonical activation of P38a MAPK. Taken together, RESV could inhibit high FFA-induced inflammatory IL-6 release mediated by P2X7 receptor through deactivation of P38 MAPK signaling pathway. All these results outline the potential mechanisms involved in the neuroprotective roles of RESV and highlight the clinical application of RESV in treatment of inflammation in relation to DNP.

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REFERENCES

  1. Lelkes, E., B.R. Unsworth, and P.I. Lelkes. 2001. Reactive oxygen species, apoptosis and altered NGF-induced signaling in PC12 pheochromocytoma cells cultured in elevated glucose: an in vitro cellular model for diabetic neuropathy. Neurotox Res 3: 189–203.

    Article  CAS  PubMed  Google Scholar 

  2. Negi, G., A. Kumar, and S.S. Sharma. 2011. Nrf2 and NF-kappaB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes. Curr Neurovasc Res 8: 294–304.

    Article  CAS  PubMed  Google Scholar 

  3. Imrie, H., A. Abbas, and M. Kearney. 2010. Insulin resistance, lipotoxicity and endothelial dysfunction. Biochim Biophys Acta 1801: 320–326.

    Article  CAS  PubMed  Google Scholar 

  4. Savary, S., D. Trompier, P. Andreoletti, F. Le Borgne, J. Demarquoy, and G. Lizard. 2012. Fatty acids-induced lipotoxicity and inflammation. Curr Drug Metab 13: 1358–70.

    Article  CAS  PubMed  Google Scholar 

  5. Diakogiannaki, E., H.J. Welters, and N.G. Morgan. 2008. Differential regulation of the endoplasmic reticulum stress response in pancreatic beta-cells exposed to long-chain saturated and monounsaturated fatty acids. J Endocrinol 197: 553–563.

    Article  CAS  PubMed  Google Scholar 

  6. Sabin, M.A., C.E. Stewart, E.C. Crowne, S.J. Turner, L.P. Hunt, G.I. Welsh, M.J. Grohmann, J.M. Holly, and J.P. Shield. 2007. Fatty acid-induced defects in insulin signalling, in myotubes derived from children, are related to ceramide production from palmitate rather than the accumulation of intramyocellular lipid. J Cell Physiol 211: 244–252.

    Article  CAS  PubMed  Google Scholar 

  7. Unger, R. H. 1995. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44: 863–870

  8. Boden, G., X. Chen, J. Ruiz, J.V. White, and L. Rossetti. 1994. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 93: 2438–2446.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Smith, A.G., and J.R. Singleton. 2012. Diabetic neuropathy. Continuum (Minneap Minn) 18: 60–84.

    Google Scholar 

  10. Vincent, A.M., J.M. Hayes, L.L. McLean, A. Vivekanandan-Giri, S. Pennathur, and E.L. Feldman. 2009. Dyslipidemia-induced neuropathy in mice: the role of oxLDL/LOX-1. Diabetes 58: 2376–2385.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Xu, H., B. Wu, F. Jiang, S. Xiong, B. Zhang, G. Li, S. Liu, Y. Gao, C. Xu, G. Tu, H. Peng, S. Liang, and H. Xiong. 2013. High fatty acids modulate P2X(7) expression and IL-6 release via the p38 MAPK pathway in PC12 cells. Brain Res Bull 94: 63–70.

    Article  CAS  PubMed  Google Scholar 

  12. Loddick, S.A., A.V. Turnbull, and N.J. Rothwell. 1998. Cerebral interleukin-6 is neuroprotective during permanent focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 18: 176–179.

    Article  CAS  PubMed  Google Scholar 

  13. Klein, M.A., J.C. Moller, L.L. Jones, H. Bluethmann, G.W. Kreutzberg, and G. Raivich. 1997. Impaired neuroglial activation in interleukin-6 deficient mice. Glia 19: 227–233.

    Article  CAS  PubMed  Google Scholar 

  14. Nakamachi, T., M. Tsuchida, N. Kagami, S. Yofu, Y. Wada, M. Hori, D. Tsuchikawa, A. Yoshikawa, N. Imai, K. Nakamura, S. Arata, and S. Shioda. 2012. IL-6 and PACAP receptor expression and localization after global brain ischemia in mice. J Mol Neurosci 48: 518–525.

    Article  CAS  PubMed  Google Scholar 

  15. Murphy, P.G., J. Grondin, M. Altares, and P.M. Richardson. 1995. Induction of interleukin-6 in axotomized sensory neurons. J Neurosci 15: 5130–5138.

    CAS  PubMed  Google Scholar 

  16. Song, D.K., Y.B. Im, J.S. Jung, H.W. Suh, S.O. Huh, J.H. Song, and Y.H. Kim. 1999. Central injection of nicotine increases hepatic and splenic interleukin 6 (IL-6) mRNA expression and plasma IL-6 levels in mice: involvement of the peripheral sympathetic nervous system. FASEB J 13: 1259–1267.

    CAS  PubMed  Google Scholar 

  17. Orellana, D.I., R.A. Quintanilla, C. Gonzalez-Billault, and R.B. Maccioni. 2005. Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons. Neurotox Res 8: 295–304.

    Article  CAS  PubMed  Google Scholar 

  18. Campbell, I.L., C.R. Abraham, E. Masliah, P. Kemper, J.D. Inglis, M.B. Oldstone, and L. Mucke. 1993. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci U S A 90: 10061–10065.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Nelson, T.E., E.A. Olde, R. Hernandez, A. Puro, S. Huitron-Resendiz, C. Hao, P.N. De Graan, and D.L. Gruol. 2012. Altered synaptic transmission in the hippocampus of transgenic mice with enhanced central nervous systems expression of interleukin-6. Brain Behav Immun 26: 959–971.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Zhu, J., X.F. Bai, E. Mix, and H. Link. 1997. Cytokine dichotomy in peripheral nervous system influences the outcome of experimental allergic neuritis: dynamics of mRNA expression for IL-1 beta, IL-6, IL-10, IL-12, TNF-alpha, TNF-beta, and cytolysin. Clin Immunol Immunopathol 84: 85–94.

    Article  CAS  PubMed  Google Scholar 

  21. Sugiyama, T. 2014. Role of P2X7 receptors in the development of diabetic retinopathy. World J Diabetes 5: 141–145.

    PubMed Central  PubMed  Google Scholar 

  22. Alves, L.A., R.J. Bezerra, R.X. Faria, L.G. Ferreira, and S.F.V. Da. 2013. Physiological roles and potential therapeutic applications of the P2X7 receptor in inflammation and pain. Molecules 18: 10953–10972.

    Article  CAS  PubMed  Google Scholar 

  23. Lister, M.F., J. Sharkey, D.A. Sawatzky, J.P. Hodgkiss, D.J. Davidson, A.G. Rossi, and K. Finlayson. 2007. The role of the purinergic P2X7 receptor in inflammation. J Inflamm (Lond) 4: 5.

    Article  Google Scholar 

  24. Di Virgilio, F., D. Ferrari, and E. Adinolfi. 2009. P2X(7): a growth-promoting receptor—implications for cancer. Purinergic Signal 5: 251–256.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Adinolfi, E., M.G. Callegari, D. Ferrari, C. Bolognesi, M. Minelli, M.R. Wieckowski, P. Pinton, R. Rizzuto, and F. Di Virgilio. 2005. Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol Biol Cell 16: 3260–3272.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Volonte, C., S. Apolloni, S.D. Skaper, and G. Burnstock. 2012. P2X7 receptors: channels, pores and more. CNS Neurol Disord Drug Targets 11: 705–721.

    Article  CAS  PubMed  Google Scholar 

  27. Solini, A., P. Chiozzi, A. Morelli, E. Adinolfi, R. Rizzo, O.R. Baricordi, and F. Di Virgilio. 2004. Enhanced P2X7 activity in human fibroblasts from diabetic patients: a possible pathogenetic mechanism for vascular damage in diabetes. Arterioscler Thromb Vasc Biol 24: 1240–1245.

    Article  CAS  PubMed  Google Scholar 

  28. Solini, A., P. Chiozzi, S. Falzoni, A. Morelli, R. Fellin, and F. Di Virgilio. 2000. High glucose modulates P2X7 receptor-mediated function in human primary fibroblasts. Diabetologia 43: 1248–1256.

    Article  CAS  PubMed  Google Scholar 

  29. Vonend, O., C.M. Turner, C.M. Chan, A. Loesch, G.C. Dell’Anna, K.S. Srai, G. Burnstock, and R.J. Unwin. 2004. Glomerular expression of the ATP-sensitive P2X receptor in diabetic and hypertensive rat models. Kidney Int 66: 157–166.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang, F., H. Wang, Q. Wu, Y. Lu, J. Nie, X. Xie, and J. Shi. 2013. Resveratrol protects cortical neurons against microglia-mediated neuroinflammation. Phytother Res 27(3): 344–349.

    Article  CAS  PubMed  Google Scholar 

  31. Sun, A.Y., Q. Wang, A. Simonyi, and G.Y. Sun. 2010. Resveratrol as a therapeutic agent for neurodegenerative diseases. Mol Neurobiol 41: 375–383.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Orsu, P., B.V. Murthy, and A. Akula. 2013. Cerebroprotective potential of resveratrol through anti-oxidant and anti-inflammatory mechanisms in rats. J Neural Transm 120: 1217–23.

    Article  CAS  PubMed  Google Scholar 

  33. Li, F., Q. Gong, H. Dong, and J. Shi. 2012. Resveratrol, a neuroprotective supplement for Alzheimer’s disease. Curr Pharm Des 18: 27–33.

    Article  PubMed  Google Scholar 

  34. Frozza, R.L., Bernardi, A., Hoppe, J.B., Meneghetti, A.B.., Battastini, A.M., Pohlmann, A.R., Guterres, S.S., and Salbego, C. 2013. Lipid-core nanocapsules improve the effects of resveratrol against Abeta-induced neuroinflammation. J Biomed Nanotechnol 9: 2086–2104.

    Article  CAS  PubMed  Google Scholar 

  35. Hirose, H., Y.H. Lee, L.R. Inman, Y. Nagasawa, J.H. Johnson, and R.H. Unger. 1996. Defective fatty acid-mediated beta-cell compensation in Zucker diabetic fatty rats. Pathogenic implications for obesity-dependent diabetes. J Biol Chem 271: 5633–5637.

    Article  CAS  PubMed  Google Scholar 

  36. Tang, Y., and G.D. Li. 2004. Chronic exposure to high glucose impairs bradykinin-stimulated nitric oxide production by interfering with the phospholipase-C-implicated signalling pathway in endothelial cells: evidence for the involvement of protein kinase C. Diabetologia 47: 2093–2104.

    Article  CAS  PubMed  Google Scholar 

  37. Livak, K.J., and T.D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25: 402–408.

    Article  CAS  PubMed  Google Scholar 

  38. Naim, M., S. Bhat, K.N. Rankin, S. Dennis, S.F. Chowdhury, I. Siddiqi, P. Drabik, T. Sulea, C.I. Bayly, A. Jakalian, and E.O. Purisima. 2007. Solvated interaction energy (SIE) for scoring protein-ligand binding affinities. 1. Exploring the parameter space. J Chem Inf Model 47: 122–133.

    Article  PubMed  Google Scholar 

  39. Chang, L., and M. Karin. 2001. Mammalian MAP kinase signalling cascades. Nature 410: 37–40.

    Article  CAS  PubMed  Google Scholar 

  40. Siddiqui, M.A., Kashyap, M.P., Kumar, V., Al-Khedhairy, A.A., Musarrat, J., and Pant, A.B.. 2010. Protective potential of trans-resveratrol against 4-hydroxynonenal induced damage in PC12 cells. Toxicol In Vitro 24: 1592–1598.

    Article  CAS  PubMed  Google Scholar 

  41. North, R.A. 2002. Molecular physiology of P2X receptors. Physiol Rev 82(4): 1013–1067.

    CAS  PubMed  Google Scholar 

  42. Zhou, H., Q. Chen, D.L. Kong, J. Guo, Q. Wang, and S.Y. Yu. 2011. Effect of resveratrol on gliotransmitter levels and p38 activities in cultured astrocytes. Neurochem Res 36: 17–26.

    Article  CAS  PubMed  Google Scholar 

  43. Han, Y., Jiang, C., Tang, J., Wang, C., Wu, P., Zhang, G., Liu, W., Jamangulova, N., Wu, X., and Song, X. 2014. Resveratrol reduces morphine tolerance by inhibiting microglial activation via AMPK signalling. Eur J Pain [Epub ahead of print]

  44. Armstrong, J.N., T.B. Brust, R.G. Lewis, and B.A. MacVicar. 2002. Activation of presynaptic P2X7-like receptors depresses mossy fiber-CA3 synaptic transmission through p38 mitogen-activated protein kinase. J Neurosci 22: 5938–5945.

    CAS  PubMed  Google Scholar 

  45. Friedle, S.A., V.M. Brautigam, M. Nikodemova, M.L. Wright, and J.J. Watters. 2011. The P2X7-Egr pathway regulates nucleotide-dependent inflammatory gene expression in microglia. Glia 59: 1–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Oliver, M.F., and L.H. Opie. 1994. Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 343: 155–158.

    Article  CAS  PubMed  Google Scholar 

  47. Ando, R.D., and B. Sperlagh. 2013. The role of glutamate release mediated by extrasynaptic P2X7 receptors in animal models of neuropathic pain. Brain Res Bull 93: 80–85.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS

This work was supported by grants (nos. 81302501, 81171184, and 31060139) from the National Natural Science Foundation of China, grants (nos. 20122BAB215005 and 20132BAB215005) from the Natural Science Foundation of Jiangxi Province, grants (nos. GJJ14093 and GJJ12149) from the Foundation of the Education Department of Jiangxi Province, and the grant from Nanchang University Students’ innovation and entrepreneurship training program.

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Authors and Affiliations

  1. Department of Physiology, JiangXi Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China

    Hong Xu, Luling He, Bing Wu, Changle Liu, Yun Gao, Guilin Li, Chunping Zhang, Shuangmei Liu, Changshui Xu, Hong Wu, Guodong Li & Shangdong Liang

  2. Department of Nursing (Foreign Nursing Class–2013 Grade), FuZhou Medical College of Nanchang University, Fuzhou, 344000, Jiangxi, People’s Republic of China

    Chaopeng Xiong

  3. Clinic experimental Class –2011 Grade, JiangXi Medical College of Nanchang University, Nanchang, 330006, Jiangxi, People’s Republic of China

    Lulu Peng & Yajun Cheng

  4. Analysis Class–2011 Grade, JiangXi Medical College of Nanchang University, Nanchang, 330006, Jiangxi, People’s Republic of China

    Fuqing Jiang & Liping Tan

  5. Clinic 6 Class–2012 Grade, JiangXi Medical College of Nanchang University, Nanchang, 330006, Jiangxi, People’s Republic of China

    Lan Tang

  6. Department of Endocrinology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, People’s Republic of China

    Yunming Tu & Yuping Yang

  7. Institute of Life Science of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China

    Shangdong Liang

  8. Department of Clinical Research, Singapore General Hospital, Singapore, 169857, Singapore

    Guodong Li

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  1. Hong Xu
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Xu, H., Xiong, C., He, L. et al. Trans-Resveratrol Attenuates High Fatty Acid-Induced P2X7 Receptor Expression and IL-6 Release in PC12 Cells: Possible Role of P38 MAPK Pathway. Inflammation 38, 327–337 (2015). https://doi.org/10.1007/s10753-014-0036-6

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