Advertisement

Inflammation

, Volume 41, Issue 2, pp 569–578 | Cite as

Overexpression of SIRT2 Alleviates Neuropathic Pain and Neuroinflammation Through Deacetylation of Transcription Factor Nuclear Factor-Kappa B

  • Yong Zhang
  • Dachao Chi
ORIGINAL ARTICLE

Abstract

Sirtuin 2 (SIRT2), a member of the mammalian sirtuin family, plays an important role in the pathogenesis of various neurological diseases. However, whether SIRT2 is involved in the regulation of neuropathic pain remains unclear. In this study, we aimed to investigate the potential role of SIRT2 in regulating neuropathic pain in a rat model induced by chronic constriction injury (CCI). We found that SIRT2 was downregulated in the dorsal root ganglion (DRG) in CCI rats. Intrathecal injection of a recombinant adenovirus expressing SIRT2 markedly alleviated mechanical allodynia and thermal hyperalgesia in CCI rats. This also inhibited the expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 in the DRG of CCI rats. Moreover, our results showed that overexpression of SIRT2 inhibited the acetylation of the nuclear factor-kappa B (NF-κB) p65 protein in the DRG of CCI rats. Additionally, treatment with a SIRT2 specific inhibitor significantly aggravated neuropathic pain and attenuated the inhibitory effect of SIRT2 overexpression on neuropathic pain development. Taken together, these results suggest that overexpression of SIRT2 alleviates neuropathic pain associated with inhibition of NF-κB signaling and neuroinflammation. Therefore, SIRT2 may serve as a potential therapeutic target for treatment of neuropathic pain.

Key Words

chronic constriction injury neuropathic pain NF-κB SIRT2 

Abbreviations

SIRT2

Sirtuin 2

CCI

Chronic constriction injury

DRG

Dorsal root ganglion

TNF-α

Tumor-necrosis factor-α

IL-1β

Interleukin

NF-κB

Nuclear factor-kappa B

FoxO1

Forkhead box O1

FOXO3a

Forkhead box 3a

Ad-SIRT2

Adenoviruses-SIRT2

RT-qPCR

Real-time quantitative polymerase chain reaction

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

BCA

Bicinchoninic acid

SDS-PAGE

Sodium dodecylsulfate-polyacrylamide gel electrophoresis

ELISA

Enzyme-linked immunosorbent assay

PWL

Paw withdrawal latencies

PWT

Paw withdrawal threshold

Notes

Compliance with Ethical Standards

This study was reviewed and approved by the Institutional Animal Care and Use Committee of Shaanxi Provincial People’s Hospital. The animal experiments were performed according to the guidelines of the International Association for the Study of Pain and the National Institute of Health Guide for the Care and Use of Laboratory Animals.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Baron, R. 2000. Peripheral neuropathic pain: from mechanisms to symptoms. The Clinical Journal of Pain 16: S12–S20.  https://doi.org/10.1097/00002508-200006001-00004.CrossRefPubMedGoogle Scholar
  2. 2.
    Sorge, R.E., T. Trang, R. Dorfman, S.B. Smith, S. Beggs, J. Ritchie, J.S. Austin, D.V. Zaykin, H. Vander Meulen, M. Costigan, et al. 2012. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nature Medicine 18: 595–599.  https://doi.org/10.1038/nm.2710.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Breivik, H., B. Collett, V. Ventafridda, R. Cohen, and D. Gallacher. 2006. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. European Journal of Pain 10: 287–333.  https://doi.org/10.1016/j.ejpain.2005.06.009.CrossRefPubMedGoogle Scholar
  4. 4.
    Bouhassira, D., M. Lanteri-Minet, N. Attal, B. Laurent, and C. Touboul. 2008. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136: 380–387.  https://doi.org/10.1016/j.pain.2007.08.013.CrossRefPubMedGoogle Scholar
  5. 5.
    O'Connor, A.B., and R.H. Dworkin. 2009. Treatment of neuropathic pain: an overview of recent guidelines. The American Journal of Medicine 122: S22–S32.  https://doi.org/10.1016/j.amjmed.2009.04.007.CrossRefPubMedGoogle Scholar
  6. 6.
    Myers, R.R., W.M. Campana, and V.I. Shubayev. 2006. The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets. Drug Discovery Today 11: 8–20.  https://doi.org/10.1016/S1359-6446(05)03637-8.CrossRefPubMedGoogle Scholar
  7. 7.
    Scholz, J., and C.J. Woolf. 2007. The neuropathic pain triad: neurons, immune cells and glia. Nature Neuroscience 10: 1361–1368.  https://doi.org/10.1038/nn1992.CrossRefPubMedGoogle Scholar
  8. 8.
    Moalem, G., and D.J. Tracey. 2006. Immune and inflammatory mechanisms in neuropathic pain. Brain Research Reviews 51: 240–264.  https://doi.org/10.1016/j.brainresrev.2005.11.004.CrossRefPubMedGoogle Scholar
  9. 9.
    Sun, T., W.G. Song, Z.J. Fu, Z.H. Liu, Y.M. Liu, and S.L. Yao. 2006. Alleviation of neuropathic pain by intrathecal injection of antisense oligonucleotides to p65 subunit of NF-kappaB. British Journal of Anaesthesia 97: 553–558.  https://doi.org/10.1093/bja/ael209.CrossRefPubMedGoogle Scholar
  10. 10.
    Houtkooper, R.H., E. Pirinen, and J. Auwerx. 2012. Sirtuins as regulators of metabolism and healthspan. Nature Reviews Molecular Cell Biology 13: 225–238.  https://doi.org/10.1038/nrm3293.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Inoue, T., M. Hiratsuka, M. Osaki, and M. Oshimura. 2007. The molecular biology of mammalian SIRT proteins: SIRT2 in cell cycle regulation. Cell Cycle 6: 1011–1018.CrossRefPubMedGoogle Scholar
  12. 12.
    Harting, K., and B. Knoll. 2010. SIRT2-mediated protein deacetylation: an emerging key regulator in brain physiology and pathology. European Journal of Cell Biology 89: 262–269.  https://doi.org/10.1016/j.ejcb.2009.11.006.CrossRefPubMedGoogle Scholar
  13. 13.
    Cha, Y.I., and H.S. Kim. 2013. Emerging role of sirtuins on tumorigenesis: possible link between aging and cancer. BMB Reports 46: 429–438.  https://doi.org/10.5483/BMBRep.2013.46.9.180.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Buechler, N., X. Wang, B.K. Yoza, C.E. McCall, and V. Vachharajani. 2017. Sirtuin 2 regulates microvascular inflammation during sepsis. Journal of Immunology Research 2017: 2648946.  https://doi.org/10.1155/2017/2648946.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Starke, R.M., R.J. Komotar, and E.S. Connolly. 2013. The role of SIRT2 in programmed necrosis: implications for stroke and neurodegenerative disorders. Neurosurgery 72: N20–N22.  https://doi.org/10.1227/01.neu.0000430740.01610.74.CrossRefGoogle Scholar
  16. 16.
    Wang, Y., Y. Mu, X. Zhou, H. Ji, X. Gao, W.W. Cai, Q. Guan, and T. Xu. 2017. SIRT2-mediated FOXO3a deacetylation drives its nuclear translocation triggering FasL-induced cell apoptosis during renal ischemia reperfusion. Apoptosis 22: 519–530.  https://doi.org/10.1007/s10495-016-1341-3.CrossRefPubMedGoogle Scholar
  17. 17.
    Zhao, Y., J. Yang, W. Liao, X. Liu, H. Zhang, S. Wang, D. Wang, J. Feng, L. Yu, and W.G. Zhu. 2010. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nature Cell Biology 12: 665–675.  https://doi.org/10.1038/ncb2069.CrossRefPubMedGoogle Scholar
  18. 18.
    Hoffmann, G., F. Breitenbucher, M. Schuler, and A.E. Ehrenhofer-Murray. 2014. A novel sirtuin 2 (SIRT2) inhibitor with p53-dependent pro-apoptotic activity in non-small cell lung cancer. Journal of Biological Chemistry 289: 5208–5216.  https://doi.org/10.1074/jbc.M113.487736.CrossRefPubMedGoogle Scholar
  19. 19.
    Rothgiesser, K.M., S. Erener, S. Waibel, B. Luscher, and M.O. Hottiger. 2010. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. Journal of Cell Science 123: 4251–4258.  https://doi.org/10.1242/jcs.073783.CrossRefPubMedGoogle Scholar
  20. 20.
    Pais, T.F., E.M. Szego, O. Marques, L. Miller-Fleming, P. Antas, P. Guerreiro, R.M. de Oliveira, B. Kasapoglu, and T.F. Outeiro. 2013. The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation. The EMBO Journal 32: 2603–2616.  https://doi.org/10.1038/emboj.2013.200.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Yuan, F., Z.M. Xu, L.Y. Lu, H. Nie, J. Ding, W.H. Ying, and H.L. Tian. 2016. SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-kappaB p65 acetylation and activation. Journal of Neurochemistry 136: 581–593.  https://doi.org/10.1111/jnc.13423.CrossRefPubMedGoogle Scholar
  22. 22.
    Yu, J., Y. Wu, and P. Yang. 2016. High glucose-induced oxidative stress represses sirtuin deacetylase expression and increases histone acetylation leading to neural tube defects. Journal of Neurochemistry 137: 371–383.  https://doi.org/10.1111/jnc.13587.CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Bennett, G.J., and Y.K. Xie. 1988. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33: 87–107.  https://doi.org/10.1016/0304-3959(88)90209-6.CrossRefPubMedGoogle Scholar
  24. 24.
    Yaksh, T.L., and T.A. Rudy. 1976. Chronic catheterization of the spinal subarachnoid space. Physiology & Behavior 17: 1031–1036.  https://doi.org/10.1016/0031-9384(76)90029-9.CrossRefGoogle Scholar
  25. 25.
    Outeiro, T.F., E. Kontopoulos, S.M. Altmann, I. Kufareva, K.E. Strathearn, A.M. Amore, C.B. Volk, M.M. Maxwell, J.C. Rochet, P.J. McLean, et al. 2007. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science 317: 516–519.  https://doi.org/10.1126/science.1143780.CrossRefPubMedGoogle Scholar
  26. 26.
    Wang, X., Q. Guan, M. Wang, L. Yang, J. Bai, Z. Yan, Y. Zhang, and Z. Liu. 2015. Aging-related rotenone-induced neurochemical and behavioral deficits: role of SIRT2 and redox imbalance, and neuroprotection by AK-7. Drug Design Development and Therapy 9: 2553–2563.CrossRefGoogle Scholar
  27. 27.
    Silva, D.F., A.R. Esteves, C.R. Oliveira, and S.M. Cardoso. 2017. Mitochondrial metabolism power SIRT2-dependent deficient traffic causing Alzheimer's-disease related pathology. Molecular Neurobiology 54: 4021–4040.  https://doi.org/10.1007/s12035-016-9951-x.CrossRefPubMedGoogle Scholar
  28. 28.
    Luthi-Carter, R., D.M. Taylor, J. Pallos, E. Lambert, A. Amore, A. Parker, H. Moffitt, D.L. Smith, H. Runne, O. Gokce, et al. 2010. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proceedings of the National Academy of Sciences of the United States of America 107: 7927–7932.  https://doi.org/10.1073/pnas.1002924107.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Erburu, M., I. Munoz-Cobo, T. Diaz-Perdigon, P. Mellini, T. Suzuki, E. Puerta, and R.M. Tordera. 2017. SIRT2 inhibition modulate glutamate and serotonin systems in the prefrontal cortex and induces antidepressant-like action. Neuropharmacology 117: 195–208.  https://doi.org/10.1016/j.neuropharm.2017.01.033.CrossRefPubMedGoogle Scholar
  30. 30.
    Liu, R., W. Dang, Y. Du, Q. Zhou, K. Jiao, and Z. Liu. 2015. SIRT2 is involved in the modulation of depressive behaviors. Scientific Reports 5: 8415.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Xie, X.Q., P. Zhang, B. Tian, and X.Q. Chen. 2016. Downregulation of NAD-dependent deacetylase SIRT2 protects mouse brain against ischemic stroke. Molecular Neurobiology.  https://doi.org/10.1093/biomet/asw035.Google Scholar
  32. 32.
    Krey, L., F. Luhder, K. Kusch, B. Czech-Zechmeister, B. Konnecke, T. Fleming Outeiro, and G. Trendelenburg. 2015. Knockout of silent information regulator 2 (SIRT2) preserves neurological function after experimental stroke in mice. Journal of Cerebral Blood Flow and Metabolism 35: 2080–2088.  https://doi.org/10.1038/jcbfm.2015.178.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Wang, X., N.L. Buechler, A. Martin, J. Wells, B. Yoza, C.E. McCall, and V. Vachharajani. 2016. Sirtuin-2 regulates sepsis inflammation in ob/ob mice. PLoS One 11: e0160431.  https://doi.org/10.1371/journal.pone.0169417.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Lo, Sasso G., K.J. Menzies, A. Mottis, A. Piersigilli, A. Perino, H. Yamamoto, K. Schoonjans, and J. Auwerx. 2014. SIRT2 deficiency modulates macrophage polarization and susceptibility to experimental colitis. PLoS One 9: e103573.  https://doi.org/10.1371/journal.pone.0114617.CrossRefGoogle Scholar
  35. 35.
    Lin, J., B. Sun, C. Jiang, H. Hong, and Y. Zheng. 2013. Sirt2 suppresses inflammatory responses in collagen-induced arthritis. Biochemical and Biophysical Research Communications 441: 897–903.  https://doi.org/10.1016/j.bbrc.2013.10.153.CrossRefPubMedGoogle Scholar
  36. 36.
    Chen, L., W. Fischle, E. Verdin, and W.C. Greene. 2001. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293: 1653–1657.  https://doi.org/10.1126/science.1062374.CrossRefGoogle Scholar
  37. 37.
    Kim, M.J., D.W. Kim, J.H. Park, S.J. Kim, C.H. Lee, J.I. Yong, E.J. Ryu, S.B. Cho, H.J. Yeo, J. Hyeon, et al. 2013. PEP-1-SIRT2 inhibits inflammatory response and oxidative stress-induced cell death via expression of antioxidant enzymes in murine macrophages. Free Radical Biology and Medicine 63: 432–445.  https://doi.org/10.1016/j.freeradbiomed.2013.06.005.CrossRefPubMedGoogle Scholar
  38. 38.
    Lee, A.S., Y.J. Jung, D. Kim, T. Nguyen-Thanh, K.P. Kang, S. Lee, S.K. Park, and W. Kim. 2014. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages. Biochemical and Biophysical Research Communications 450: 1363–1369.  https://doi.org/10.1016/j.bbrc.2014.06.135.CrossRefPubMedGoogle Scholar
  39. 39.
    Chen, H., D. Wu, X. Ding, and W. Ying. 2015. SIRT2 is required for lipopolysaccharide-induced activation of BV2 microglia. Neuroreport 26: 88–93.  https://doi.org/10.1097/WNR.0000000000000305.CrossRefPubMedGoogle Scholar
  40. 40.
    Wang, B., Y. Zhang, W. Cao, X. Wei, J. Chen, and W. Ying. 2016. SIRT2 plays significant roles in lipopolysaccharides-induced neuroinflammation and brain injury in mice. Neurochemical Research 41: 2490–2500.  https://doi.org/10.1007/s11064-016-1981-2.CrossRefPubMedGoogle Scholar
  41. 41.
    Szego, E.M., E. Gerhardt, and T.F. Outeiro. 2017. Sirtuin 2 enhances dopaminergic differentiation via the AKT/GSK-3beta/beta-catenin pathway. Neurobiology of Aging 56: 7–16.  https://doi.org/10.1016/j.neurobiolaging.2017.04.001.CrossRefPubMedGoogle Scholar
  42. 42.
    Park, J.H., C.K. Kim, S.B. Lee, K.H. Lee, S.W. Cho, and J.Y. Ahn. 2016. Akt attenuates apoptotic death through phosphorylation of H2A under hydrogen peroxide-induced oxidative stress in PC12 cells and hippocampal neurons. Scientific Reports 6: 21857.CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Fu, Z., and J. Shi. 2017. Differential expression of tubulin acetylase and deacetylase between the damaged dentral and peripheral branch of dorsal root ganglion neurons. Medical Science Monitor 23: 3673–3678.  10.12659/MSM.902829.CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Valle, C., I. Salvatori, V. Gerbino, S. Rossi, L. Palamiuc, F. Rene, and M.T. Carri. 2014. Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways. Cell Death & Disease 5: e1296.  https://doi.org/10.1038/cddis.2014.247.CrossRefGoogle Scholar
  45. 45.
    Maxwell, M.M., E.M. Tomkinson, J. Nobles, J.W. Wizeman, A.M. Amore, L. Quinti, V. Chopra, S.M. Hersch, and A.G. Kazantsev. 2011. The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS. Human Molecular Genetics 20: 3986–3996.  https://doi.org/10.1093/hmg/ddr326.CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Ma, B., J. Shi, L. Jia, W. Yuan, J. Wu, Z. Fu, Y. Wang, N. Liu, and Z. Guan. 2013. Over-expression of PUMA correlates with the apoptosis of spinal cord cells in rat neuropathic intermittent claudication model. PLoS One 8: e56580.  https://doi.org/10.1371/journal.pone.0084903.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of AcupunctureShaanxi Provincial People’s HospitalXi’anChina
  2. 2.Department of General SurgeryShaanxi Provincial People’s HospitalXi’anChina

Personalised recommendations