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Effects of Salicylate on the Inflammatory Genes Expression and Synaptic Ultrastructure in the Cochlear Nucleus of Rats

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Abstract

Aspirin (salicylate), as a common drug that is frequently used for long-term treatment in a clinical setting, has the potential to cause reversible tinnitus. However, few reports have examined the inflammatory cytokines expression and alteration of synaptic ultrastructure in the cochlear nucleus (CN) in a rat model of tinnitus. The tinnitus-like behavior of rats were detected by the gap prepulse inhibition of acoustic startle (GPIAS) paradigm. We investigated the expression levels of the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), N-methyl d-aspartate receptor subunit 2A (NR2A) mRNA and protein in the CN and compared synapses ultrastructure in the CN of tinnitus rats with normal ones. GPIAS showed that rats with long-term administration of salicylate were experiencing tinnitus, and the mRNA and protein expression levels of TNF-α and NR2A were up-regulated in chronic treatment groups, and they returned to baseline 14 days after cessation of treatment. Furthermore, compared to normal rats, repetitive salicylate-treated rats showed a greater number of presynaptic vesicles, thicker and longer postsynaptic densities, increased synaptic interface curvature. These data revealed that chronic salicylate administration markedly, but reversibly, induces tinnitus possibly via augmentation of the expression of TNF-α and NR2A and cause changes in synaptic ultrastructure in the CN. Long-term administration of salicylate causes neural plasticity changes at the CN level.

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Abbreviations

CN:

Cochlear nucleus

TNF-α:

Tumor necrosis factor-α

IL-6:

Interleukin-6

NMDA:

N-methyl-d-aspartate

NR2A:

N-methyl d-aspartate receptor subunit 2A

GPIAS:

gap prepulse inhibition of acoustic startle

References

  1. Bartels, H., M.J. Staal, and F.W. Albers. 2007. Tinnitus and neural plasticity of the brain. Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society and European Academy of Otology and Neurotology 28(2): 178–184.

    Article  Google Scholar 

  2. Jastreboff, P.J., J.F. Brennan, J.K. Coleman, and C.T. Sasaki. 1988. Phantom auditory sensation in rats: an animal model for tinnitus. Behavioral Neuroscience 102(6): 811–822.

    Article  CAS  PubMed  Google Scholar 

  3. Paul, A.K., E. Lobarinas, R. Simmons, D. Wack, J.C. Luisi, J. Spernyak, et al. 2009. Metabolic imaging of rat brain during pharmacologically-induced tinnitus. NeuroImage 44(2): 312–318.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Yu, N., M.L. Zhu, B. Johnson, Y.P. Liu, R.O. Jones, and H.B. Zhao. 2008. Prestin up-regulation in chronic salicylate (aspirin) administration: an implication of functional dependence of prestin expression. Cellular and Molecular Life Sciences: CMLS 65(15): 2407–2418.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Huang, Z.W., Y. Luo, Z. Wu, Z. Tao, R.O. Jones, and H.B. Zhao. 2005. Paradoxical enhancement of active cochlear mechanics in long-term administration of salicylate. Journal of Neurophysiology 93(4): 2053–2061.

    Article  CAS  PubMed  Google Scholar 

  6. Yang, K., Z.W. Huang, Z.Q. Liu, B.K. Xiao, and J.H. Peng. 2009. Long-term administration of salicylate enhances prestin expression in rat cochlea. International Journal of Audiology 48(1): 18–23.

    Article  PubMed  Google Scholar 

  7. Cazals, Y., and Z.W. Huang. 1996. Average spectrum of cochlear activity: a possible synchronized firing, its olivo-cochlear feedback and alterations under anesthesia. Hearing Research 101(1–2): 81–92.

    Article  CAS  PubMed  Google Scholar 

  8. Cazals, Y., K.C. Horner, and Z.W. Huang. 1998. Alterations in average spectrum of cochleoneural activity by long-term salicylate treatment in the guinea pig: a plausible index of tinnitus. Journal of Neurophysiology 80(4): 2113–2120.

    CAS  PubMed  Google Scholar 

  9. Ruel, J., C. Chabbert, R. Nouvian, R. Bendris, M. Eybalin, C.L. Leger, et al. 2008. Salicylate enables cochlear arachidonic-acid-sensitive NMDA receptor responses. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 28(29): 7313–7323.

    Article  CAS  Google Scholar 

  10. Guitton, M.J., and Y. Dudai. 2007. Blockade of cochlear NMDA receptors prevents long-term tinnitus during a brief consolidation window after acoustic trauma. Neural Plasticity 2007: 80904.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Park, H.J., H.J. Kim, G.S. Bae, S.W. Seo, D.Y. Kim, W.S. Jung, et al. 2009. Selective GSK-3beta inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells. Hearing Research 257(1–2): 53–62.

    Article  CAS  PubMed  Google Scholar 

  12. Fujioka, M., S. Kanzaki, H.J. Okano, M. Masuda, K. Ogawa, and H. Okano. 2006. Proinflammatory cytokines expression in noise-induced damaged cochlea. Journal of Neuroscience Research 83(4): 575–583.

    Article  CAS  PubMed  Google Scholar 

  13. Sun, Y.E., L. Peng, X. Sun, J. Bo, D. Yang, Y. Zheng, et al. 2012. Intrathecal injection of spironolactone attenuates radicular pain by inhibition of spinal microglia activation in a rat model. PloS ONE 7(6): e39897.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Butterworth, R.F. 2008. Pathophysiology of hepatic encephalopathy: the concept of synergism. Hepatology Research: The official journal of the Japan Society of Hepatology 38(Suppl 1): S116–S121.

    Article  CAS  Google Scholar 

  15. Kawasaki, Y., L. Zhang, J.K. Cheng, and R.R. Ji. 2008. Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 28(20): 5189–5194.

    Article  CAS  Google Scholar 

  16. Nakazawa, T. 2009. Mechanism of N-methyl-D-aspartate-induced retinal ganglion cell death. Nippon Ganka Gakkai Zasshi 113(11): 1060–1070.

    CAS  PubMed  Google Scholar 

  17. Saunders, J.C. 2007. The role of central nervous system plasticity in tinnitus. Journal of Communication Disorders 40(4): 313–334.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Kaltenbach, J.A., and D.A. Godfrey. 2008. Dorsal cochlear nucleus hyperactivity and tinnitus: are they related? American Journal of Audiology 17(2): S148–S161.

    Article  PubMed  Google Scholar 

  19. Baizer, J.S., S. Manohar, N.A. Paolone, N. Weinstock, and R.J. Salvi. 2012. Understanding tinnitus: the dorsal cochlear nucleus, organization and plasticity. Brain Research 1485: 40–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Kaltenbach, J.A., M.A. Zacharek, J. Zhang, and S. Frederick. 2004. Activity in the dorsal cochlear nucleus of hamsters previously tested for tinnitus following intense tone exposure. Neuroscience Letters 355(1–2): 121–125.

    Article  CAS  PubMed  Google Scholar 

  21. Robertson, D., C. Bester, D. Vogler, and W.H. Mulders. 2013. Spontaneous hyperactivity in the auditory midbrain: relationship to afferent input. Hearing Research 295: 124–129.

    Article  PubMed  Google Scholar 

  22. Vogler, D.P., D. Robertson, and W.H. Mulders. 2011. Hyperactivity in the ventral cochlear nucleus after cochlear trauma. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 31(18): 6639–6645.

    Article  CAS  Google Scholar 

  23. Lobarinas, E., S.H. Hayes, and B.L. Allman. 2013. The gap-startle paradigm for tinnitus screening in animal models: limitations and optimization. Hearing Research 295: 150–160.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Engineer, N.D., J.R. Riley, J.D. Seale, W.A. Vrana, J.A. Shetake, S.P. Sudanagunta, et al. 2011. Reversing pathological neural activity using targeted plasticity. Nature 470(7332): 101–104.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Yang, G., E. Lobarinas, L. Zhang, J. Turner, D. Stolzberg, R. Salvi, et al. 2007. Salicylate induced tinnitus: behavioral measures and neural activity in auditory cortex of awake rats. Hearing Research 226(1–2): 244–253.

    Article  CAS  PubMed  Google Scholar 

  26. Su, Y.Y., B. Luo, Y. Jin, S.H. Wu, E. Lobarinas, R.J. Salvi, et al. 2012. Altered neuronal intrinsic properties and reduced synaptic transmission of the rat's medial geniculate body in salicylate-induced tinnitus. PloS ONE 7(10): e46969.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. 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(4): 402–408.

    Article  CAS  PubMed  Google Scholar 

  28. Guldner, F.H., and C.A. Ingham. 1980. Increase in postsynaptic density material in optic target neurons of the rat suprachiasmatic nucleus after bilateral enucleation. Neuroscience Letters 17(1–2): 27–31.

    Article  CAS  PubMed  Google Scholar 

  29. Keithley, E.M., X. Wang, and G.C. Barkdull. 2008. Tumor necrosis factor alpha can induce recruitment of inflammatory cells to the cochlea. Otology & Neurotology: Official Publication of the American Otological Society, American Neurotology Society and European Academy of Otology and Neurotology 29(6): 854–859.

    Article  Google Scholar 

  30. Wakabayashi, K., M. Fujioka, S. Kanzaki, H.J. Okano, S. Shibata, D. Yamashita, et al. 2010. Blockade of interleukin-6 signaling suppressed cochlear inflammatory response and improved hearing impairment in noise-damaged mice cochlea. Neuroscience Research 66(4): 345–352.

    Article  CAS  PubMed  Google Scholar 

  31. Hwang, J.H., J.C. Chen, and Y.C. Chan. 2013. Effects of C-phycocyanin and Spirulina on salicylate-induced tinnitus, expression of NMDA receptor and inflammatory genes. PloS ONE 8(3): e58215.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Hwang, J.H., J.C. Chen, S.Y. Yang, M.F. Wang, and Y.C. Chan. 2011. Expression of tumor necrosis factor-alpha and interleukin-1beta genes in the cochlea and inferior colliculus in salicylate-induced tinnitus. Journal of Neuroinflammation 8: 30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Park, K.M., and W.J. Bowers. 2010. Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cellular Signalling 22(7): 977–983.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Weber, C., P. Arck, B. Mazurek, and B.F. Klapp. 2002. Impact of a relaxation training on psychometric and immunologic parameters in tinnitus sufferers. Journal of Psychosomatic Research 52(1): 29–33.

    Article  PubMed  Google Scholar 

  35. Budd, R.J., and R. Pugh. 1995. The relationship between locus of control, tinnitus severity, and emotional distress in a group of tinnitus sufferers. Journal of Psychosomatic Research 39(8): 1015–1018.

    Article  CAS  PubMed  Google Scholar 

  36. McAfoose, J., and B.T. Baune. 2009. Evidence for a cytokine model of cognitive function. Neuroscience and Biobehavioral Reviews 33(3): 355–366.

    Article  CAS  PubMed  Google Scholar 

  37. Seidel, A., V. Arolt, M. Hunstiger, L. Rink, A. Behnisch, and H. Kirchner. 1995. Cytokine production and serum proteins in depression. Scandinavian Journal of Immunology 41(6): 534–538.

    Article  CAS  PubMed  Google Scholar 

  38. Guitton, M.J., J. Caston, J. Ruel, R.M. Johnson, R. Pujol, and J.L. Puel. 2003. Salicylate induces tinnitus through activation of cochlear NMDA receptors. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 23(9): 3944–3952.

    CAS  Google Scholar 

  39. Peng, B.G., S. Chen, and X. Lin. 2003. Aspirin selectively augmented N-methyl-d-aspartate types of glutamate responses in cultured spiral ganglion neurons of mice. Neuroscience Letters 343(1): 21–24.

    Article  CAS  PubMed  Google Scholar 

  40. Kaltenbach, J.A., J. Zhang, and P. Finlayson. 2005. Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus. Hearing Research 206(1–2): 200–226.

    Article  PubMed  Google Scholar 

  41. Sahley, T.L., M.D. Hammonds, and F.E. Musiek. 2013. Endogenous dynorphins, glutamate and N-methyl-d-aspartate (NMDA) receptors may participate in a stress-mediated Type-I auditory neural exacerbation of tinnitus. Brain Research 1499: 80–108.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81170917, No.30973298) and the Creative Project of the Shanghai Municipal Education Committee (No. 12ZZ103) to Zhi-Wu Huang.

Competing interests

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China

    Shou-Sen Hu, Ling Mei, Jian-Yong Chen, Zhi-Wu Huang & Hao Wu

  2. Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China

    Shou-Sen Hu, Ling Mei, Jian-Yong Chen, Zhi-Wu Huang & Hao Wu

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  1. Shou-Sen Hu
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  2. Ling Mei
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Correspondence to Zhi-Wu Huang.

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Hu, SS., Mei, L., Chen, JY. et al. Effects of Salicylate on the Inflammatory Genes Expression and Synaptic Ultrastructure in the Cochlear Nucleus of Rats. Inflammation 37, 365–373 (2014). https://doi.org/10.1007/s10753-013-9748-2

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