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Melatonin Improves Bladder Symptoms and May Ameliorate Bladder Damage via Increasing HO-1 in Rats

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Abstract

This study aims to investigate the efficacy and possible mechanisms of melatonin in treating interstitial cystitis (IC), as melatonin is involved in anti-inflammatory and immunomodulatory effects and plays an important role in neuroprotection. IC was induced by intraperitoneal injection of cyclophosphamide (CP) with melatonin pretreatment or vehicle pretreatment. On day 7, the voiding behaviors were observed. Bladders were harvested for histologic examination, analysis of the expressions of heme oxygenase-1 (HO-1) and inducible nitric oxide synthase (iNOS) by Western blotting, and also processed for immunohistochemical staining of substance P (SP). Proinflammatory cytokines were measured by ELISA immunoassays. L6-S1 spinal cords were harvested for measurement of SP by radioimmunoassay. CP injection resulted in severe cystitis with increase in voiding behaviors, histological damage, mast cell proliferation, SP, and proinflammatory cytokine expression, which were significantly downregulated by melatonin pretreatment. Pretreatment with melatonin further enhanced the expression of HO-1 and significantly reduced iNOS expression. Melatonin significantly improved bladder symptoms and histological damages in rats with CP-induced cystitis by diminishing bladder oxidative stress, blocking iNOS, upregulation of HO-1, and downregulating the expression of SP.

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References

  1. Pandi-Perumal, S.R., V. Srinivasan, G.J. Maestroni, et al. 2006. Melatonin: nature’s most versatile biological signal? FEBS Journal 273: 2813–38.

    Article  PubMed  CAS  Google Scholar 

  2. Berson, D.M., F.A. Dunn, and M. Takao. 2002. Phototransduction by retinal ganglion cells that set the circadian clock. Science 295: 1070–3.

    Article  PubMed  CAS  Google Scholar 

  3. Reiter, R.J., D.X. Tan, J.C. Mayo, et al. 2003. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochimica Polonica 50: 1129–46.

    PubMed  CAS  Google Scholar 

  4. Kwon, K.J., J.N. Kim, M.K. Kim, et al. 2011. Melatonin synergistically increases resveratrol-induced heme oxygenase-1 expression through the inhibition of ubiquitin-dependent proteasome pathway: a possible role in neuroprotection. Journal of Pineal Research 50: 110–23.

    PubMed  CAS  Google Scholar 

  5. Giannantoni, A., E. Costantini, S.M. Di Stasi, et al. 2006. Botulinum A toxin intravesical injections in the treatment of painful bladder syndrome: a pilot study. European Urology 49: 704–9.

    Article  PubMed  CAS  Google Scholar 

  6. Erickson, D.R. 2012. Identifying biomarkers for interstitial cystitis/bladder pain syndrome. Journal of Urology 187: 1958–9.

    Article  PubMed  Google Scholar 

  7. Meng, E., J.S. Young, T.L. Cha, et al. 2012. Neuronal-derived nitric oxide modulates the activity of mouse detrusor smooth muscle. Neurourology and Urodynamics 31: 572–8.

    Article  PubMed  CAS  Google Scholar 

  8. Giannantoni, A., V. Bini, R. Dmochowski, et al. 2012. Contemporary management of the painful bladder: a systematic review. European Urology 61: 29–53.

    Article  PubMed  Google Scholar 

  9. Pozo, M.J., P.J. Gomez-Pinilla, C. Camello-Almaraz, et al. 2010. Melatonin, a potential therapeutic agent for smooth muscle-related pathological conditions and aging. Current Medicinal Chemistry 17: 4150–65.

    Article  PubMed  CAS  Google Scholar 

  10. Terry, P.D., F. Villinger, G.A. Bubenik, et al. 2009. Melatonin and ulcerative colitis: evidence, biological mechanisms, and future research. Inflammatory Bowel Diseases 15: 134–40.

    Article  PubMed  Google Scholar 

  11. Srinivasan, V., S.R. Pandi-Perumal, I. Trahkt, et al. 2009. Melatonin and melatonergic drugs on sleep: possible mechanisms of action. International Journal of Neuroscience 119: 821–46.

    Article  PubMed  CAS  Google Scholar 

  12. He, H., W. Dong, and F. Huang. 2010. Anti-amyloidogenic and anti-apoptotic role of melatonin in Alzheimer disease. Current Neuropharmacology 8: 211–7.

    Article  PubMed  CAS  Google Scholar 

  13. Kovács, J., W. Brodner, V. Kirchlechner, et al. 2000. Measurement of urinary melatonin: a useful tool for monitoring serum melatonin after its oral administration. Journal of Clinical Endocrinology and Metabolism 85: 666–70.

    Article  PubMed  Google Scholar 

  14. Cetinel, S., F. Ercan, E. Cikler, et al. 2005. Protective effect of melatonin on water avoidance stress induced degeneration of the bladder. Journal of Urology 173: 267–70.

    Article  PubMed  CAS  Google Scholar 

  15. Kageyama, A., T. Fujino, Y. Taki, et al. 2008. Alteration of muscarinic and purinergic receptors in urinary bladder of rats with cyclophosphamide-induced interstitial cystitis. Neuroscience Letters 436: 81–4.

    Article  PubMed  CAS  Google Scholar 

  16. Kumar, A., and A. Singh. 2009. Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behaviour modification and oxidative damage in mice. Fundamental and Clinical Pharmacology 23: 439–48.

    Article  PubMed  CAS  Google Scholar 

  17. Dickson, A., A. Avelino, F. Cruz, et al. 2006. Peptidergic sensory and parasympathetic fiber sprouting in the mucosa of the rat urinary bladder in a chronic model of cyclophosphamide-induced cystitis. Neuroscience 141: 1633–47.

    Article  PubMed  CAS  Google Scholar 

  18. Rudick, C.N., P.J. Bryce, L.A. Guichelaar, et al. 2008. Mast cell-derived histamine mediates cystitis pain. PLoS One 3: e2096.

    Article  PubMed  Google Scholar 

  19. Zhang, Q.H., X.C. Shen, Z.S. Zhou, et al. 2010. Decreased nanobacteria levels and symptoms of nanobacteria-associated interstitial cystitis/painful bladder syndrome after tetracycline treatment. International Urogynecology Journal 21: 103–9.

    Article  PubMed  Google Scholar 

  20. Westropp, J.L., and C.A. Buffington. 2002. In vivo models of interstitial cystitis. Journal of Urology 167: 694–702.

    Google Scholar 

  21. Wantuch, C., M. Piesla, and L. Leventhal. 2007. Pharmacological validation of a model of cystitis pain in the mouse. Neuroscience Letters 421: 250–2.

    Article  PubMed  CAS  Google Scholar 

  22. Joshi, S.K., J.P. Mikusa, B. Weaver, et al. 2008. Morphine and ABT-594 (a nicotinic acetylcholine agonist) exert centrally mediated antinociception in the rat cyclophosphamide cystitis model of visceral pain. The Journal of Pain 9: 146–56.

    Article  PubMed  CAS  Google Scholar 

  23. Topal, T., Y. Oztas, A. Korkmaz, et al. 2005. Melatonin ameliorates bladder damage induced by cyclophosphamide in rats. Journal of Pineal Research 38: 272–7.

    Article  PubMed  CAS  Google Scholar 

  24. Matsuoka, Y., H. Masuda, M. Yokoyama, et al. 2007. Protective effects of heme oxygenase-1 against cyclophosphamide-induced haemorrhagic cystitis in rats. BJU International 100: 1402–8.

    Article  PubMed  CAS  Google Scholar 

  25. Ochodnický, P., C.D. Cruz, N. Yoshimura, and M.C. Michel. 2011. Nerve growth factor in bladder dysfunction: contributing factor, biomarker, and therapeutic target. Neurourology and Urodynamics 30: 1227–41.

    PubMed  Google Scholar 

  26. Cervero, F., and J.M. Laird. 1999. Visceral pain. Lancet 353: 2145–8.

    Article  PubMed  CAS  Google Scholar 

  27. Korkmaz, A., R.J. Reiter, T. Topal, et al. 2009. Melatonin: an established antioxidant worthy of use in clinical trials. Molecular Medicine 15: 43–50.

    PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the National Natural Science Foundation of China no. 81000241.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Daping Hospital, Third Military Medical University, Daping, Yuzhong District, Chongqing, 400038, People’s Republic of China

    Qing-hua Zhang & Jian-xin Guo

  2. Urological Research Institute of PLA, Southwest Hospital, Third Military Medical University, Chongqing, 400038, People’s Republic of China

    Zhan-song Zhou, Gen-sheng Lu & Bo Song

Authors
  1. Qing-hua Zhang
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  2. Zhan-song Zhou
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  3. Gen-sheng Lu
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  4. Bo Song
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  5. Jian-xin Guo
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Correspondence to Jian-xin Guo.

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Zhang, Qh., Zhou, Zs., Lu, Gs. et al. Melatonin Improves Bladder Symptoms and May Ameliorate Bladder Damage via Increasing HO-1 in Rats. Inflammation 36, 651–657 (2013). https://doi.org/10.1007/s10753-012-9588-5

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  • DOI: https://doi.org/10.1007/s10753-012-9588-5

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