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Inflammation

, Volume 41, Issue 2, pp 515–529 | Cite as

Short- and Long-Term Protective Effects of Melatonin in a Mouse Model of Sepsis-Associated Encephalopathy

  • Mu-huo Ji
  • De-guo Xia
  • Lan-yue Zhu
  • Xia Zhu
  • Xiao-yan Zhou
  • Jiang-yan Xia
  • Jian-jun Yang
ORIGINAL ARTICLE

Abstract

Brain dysfunction is a common complication after sepsis and is an independent risk factor for a poor prognosis, which is partly attributed to the dysregulated inflammatory response and oxidative damage. Melatonin regulates the sleep–wake cycle and also has potent anti-inflammatory and antioxidant properties, yet the protective effects of melatonin on sepsis-induced neurobehavioral dysfunction remain to be elucidated. In the present study, melatonin was administered intraperitoneally daily at a dose of 10 mg/kg for three consecutive days immediately (early treatment) or 7 days (delayed treatment) after sham operation or cecal ligation and puncture (CLP), followed by an additional treatment in drinking water until the end of behavioral tests. The concentrations of pro-inflammatory cytokines (tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10), malondialdehyde (MDA), superoxide dismutase (SOD), reactive oxygen species (ROS), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) were determined at the indicated time points. Compared with the CLP + vehicle group, we found that early melatonin treatment resulted in increased survival rate but not improvement in measures of neurobehavioral outcomes, which was accompanied by significantly lower plasma level of IL-1β. Intriguingly, delayed melatonin treatment improved neurobehavioral dysfunction by normalization of hippocampal BDNF and GDNF expressions. In conclusion, our study suggests the beneficial effects of both early and delayed melatonin treatment after sepsis development, which implicates melatonin has a potential therapeutic value in sepsis-associated organ damage including brain dysfunction.

KEY WORDS

sepsis melatonin cognitive function neuroplasticity 

Notes

Funding

This study was supported by grants from the National Science Foundation of China (Nos. 81471105, 81771156, 81772126) and Jiangsu Provincial Medical Youth Talent (QNRC2016822).

Compliance with Ethical Standards

The study protocol was approved by the Ethics Committee of the Nanjing Integrated Traditional Chinese and Western Medicine Hospital, affiliated with the Nanjing University of Chinese Medicine, and all procedures were performed in accordance with the Guideline for the Care and Use of Laboratory Animals from the National Institutes of Health, USA.

Conflict of Interest

The authors declare that they have no competing interests.

References

  1. 1.
    Gofton, T.E., and G.B. Young. 2012. Sepsis-associated encephalopathy. Nature Reviews. Neurology 8 (10): 557–566.CrossRefPubMedGoogle Scholar
  2. 2.
    Iwashyna, T.J., E.W. Ely, D.M. Smith, and K.M. Langa. 2010. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304 (16): 1787–1794.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Widmann, C.N., and M.T. Heneka. 2014. Long-term cerebral consequences of sepsis. Lancet Neurology 13 (6): 630–636.CrossRefPubMedGoogle Scholar
  4. 4.
    Pandharipande, P.P., T.D. Girard, J.C. Jackson, A. Morandi, J.L. Thompson, B.T. Pun, N.E. Brummel, C.G. Hughes, E.E. Vasilevskis, A.K. Shintani, K.G. Moons, S.K. Geevarghese, A. Canonico, R.O. Hopkins, G.R. Bernard, R.S. Dittus, E.W. Ely, and BRAIN-ICU Study Investigators. 2013. Long-term cognitive impairment after critical illness. The New England Journal of Medicine 369 (14): 1306–1316.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Girard, T.D., J.C. Jackson, P.P. Pandharipande, B.T. Pun, J.L. Thompson, A.K. Shintani, S.M. Gordon, A.E. Canonico, R.S. Dittus, G.R. Bernard, and E.W. Ely. 2010. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Critical Care Medicine 38 (7): 1513–1520.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Czerniawski, J., and J.F. Guzowski. 2014. Acute neuroinflammation impairs context discrimination memory and disrupts pattern separation processes in hippocampus. The Journal of Neuroscience 34 (37): 12470–12480.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Wu, J., L. Dong, M. Zhang, M. Jia, G. Zhang, L. Qiu, M. Ji, and J. Yang. 2013. Class I histone deacetylase inhibitor valproic acid reverses cognitive deficits in a mouse model of septic encephalopathy. Neurochemical Research 38 (11): 2440–2449.CrossRefPubMedGoogle Scholar
  8. 8.
    Ji, M.H., L.L. Qiu, H. Tang, L.S. Ju, X.R. Sun, H. Zhang, M. Jia, Z.Y. Zuo, J.C. Shen, and J.J. Yang. 2015. Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice. Journal of Neuroinflammation 12: 182.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lowes, D.A., A.M. Almawash, N.R. Webster, V.L. Reid, and H.F. Galley. 2011. Melatonin and structurally similar compounds have differing effects on inflammation and mitochondrial function in endothelial cells under conditions mimicking sepsis. British Journal of Anaesthesia 107 (2): 193–201.CrossRefPubMedGoogle Scholar
  10. 10.
    Madrid-Navarro, C.J., R. Sanchez-Galvez, A. Martinez-Nicolas, R. Marina, J.A. Garcia, J.A. Madrid, and M.A. Rol. 2015. Disruption of circadian rhythms and delirium, sleep impairment and sepsis in critically ill patients. Potential therapeutic implications for increased light-dark contrast and melatonin therapy in an ICU environment. Current Pharmaceutical Design 21 (24): 3453–3468.CrossRefPubMedGoogle Scholar
  11. 11.
    Soleimani, E., I. Goudarzi, K. Abrari, and T. Lashkarbolouki. 2017. Maternal administration of melatonin prevents spatial learning and memory deficits induced by developmental ethanol and lead co-exposure. Physiology & Behavior 173: 200–208.CrossRefGoogle Scholar
  12. 12.
    Verceles, A.C., L. Silhan, M. Terrin, G. Netzer, C. Shanholtz, and S.M. Scharf. 2012. Circadian rhythm disruption in severe sepsis: The effect of ambient light on urinary 6-sulfatoxymelatonin secretion. Intensive Care Medicine 38 (5): 804–810.CrossRefPubMedGoogle Scholar
  13. 13.
    Lowes, D.A., N.R. Webster, M.P. Murphy, and H.F. Galley. 2013. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. British Journal of Anaesthesia 110 (3): 472–480.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    De Filippis, D., T. Iuvone, G. Esposito, L. Steardo, G.H. Arnold, A.P. Paul, Joris G. De Man, and Y. De Winter Benedicte. 2008. Melatonin reverses lipopolysaccharide-induced gastro-intestinal motility disturbances through the inhibition of oxidative stress. Journal of Pineal Research 44 (1): 45–51.PubMedGoogle Scholar
  15. 15.
    Yu L, Fan C, Li Z, Zhang J, Xue X, Xu Y, Zhao G, Yang Y, Wang H. 2017. Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. J Pineal Res 62(1).Google Scholar
  16. 16.
    Yip, H.K., C.C. Yang, K.H. Chen, T.H. Huang, Y.L. Chen, Y.Y. Zhen, P.H. Sung, H.J. Chiang, J.J. Sheu, C.L. Chang, C.H. Chen, H.W. Chang, and Y.T. Chen. 2015. Combined melatonin and exendin-4 therapy preserves renal ultrastructural integrity after ischemia-reperfusion injury in the male rat. Journal of Pineal Research 59 (4): 434–447.CrossRefPubMedGoogle Scholar
  17. 17.
    Yang, B., Y.F. Ni, W.C. Wang, H.Y. Du, H. Zhang, L. Zhang, W.D. Zhang, and T. Jiang. 2015. Melatonin attenuates intestinal ischemia—reperfusion-induced lung injury in rats by upregulating N-myc downstream-regulated gene 2. The Journal of Surgical Research 194 (1): 273–280.CrossRefPubMedGoogle Scholar
  18. 18.
    Feng D, Wang B, Wang L, Abraham N, Tao K, Huang L, Shi W, Dong Y, Qu Y. 2017. Pre-ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress-dependent autophagy via PERK and IRE1 signalings. J Pineal Res 62(3).Google Scholar
  19. 19.
    Park G, Lee SH, Oh DS, Kim YU. 2017. Melatonin inhibits neuronal dysfunction-associated with neuroinflammation by atopic psychological stress in NC/Nga atopic-like mouse models. J Pineal Res.Google Scholar
  20. 20.
    Fan, Y., L. Yuan, M. Ji, J. Yang, and D. Gao. 2017. The effect of melatonin on early postoperative cognitive decline in elderly patients undergoing hip arthroplasty: A randomized controlled trial. Journal of Clinical Anesthesia 39: 77–81.CrossRefPubMedGoogle Scholar
  21. 21.
    Iggena D, Winter Y, Steiner B. 2017. Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice. J Pineal Res 62(4).Google Scholar
  22. 22.
    Zhang, H., D. Liu, X. Wang, X. Chen, Y. Long, W. Chai, X. Zhou, X. Rui, Q. Zhang, H. Wang, and Q. Yang. 2013. Melatonin improved rat cardiac mitochondria and survival rate in septic heart injury. Journal of Pineal Research 55 (1): 1–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Hu, W., C. Deng, Z. Ma, D. Wang, C. Fan, T. Li, S. Di, B. Gong, R.J. Reiter, and Y. Yang. 2017. Utilizing melatonin to combat bacterial infections and septic injury. British Journal of Pharmacology 174 (9): 754–768.CrossRefPubMedGoogle Scholar
  24. 24.
    Wang, X., G.X. Xue, W.C. Liu, H. Shu, M. Wang, Y. Sun, X. Liu, Y.E. Sun, C.F. Liu, J. Liu, W. Liu, and X. Jin. 2017. Melatonin alleviates lipopolysaccharide-compromised integrity of blood-brain barrier through activating AMP-activated protein kinase in old mice. Aging Cell 16 (2): 414–421.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Anderson, S.T., S. Commins, P.N. Moynagh, and A.N. Coogan. 2015. Lipopolysaccharide-induced sepsis induces long-lasting affective changes in the mouse. Brain, Behavior, and Immunity 43: 98–109.CrossRefPubMedGoogle Scholar
  26. 26.
    Wu, J., M. Zhang, S. Hao, M. Jia, M. Ji, L. Qiu, X. Sun, J. Yang, and K. Li. 2015. Mitochondria-targeted peptide reverses mitochondrial dysfunction and cognitive deficits in sepsis-associated encephalopathy. Molecular Neurobiology 52 (1): 783–791.CrossRefPubMedGoogle Scholar
  27. 27.
    Liu, L., K. Xie, H. Chen, X. Dong, Y. Li, Y. Yu, G. Wang, and Y. Yu. 2014. Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis. Brain Research 1589: 78–92.CrossRefPubMedGoogle Scholar
  28. 28.
    Della Giustina A, Goldim MP, Danielski LG, Florentino D, Mathias K, Garbossa L, Oliveira Junior AN, Fileti ME, Zarbato GF, da Rosa N, Martins Laurentino AO, Fortunato JJ, Mina F, Bellettini-Santos T, Budni J, Barichello T, Dal-Pizzol F, Petronilho F. 2017. Alpha-lipoic acid attenuates acute neuroinflammation and long-term cognitive impairment after polymicrobial sepsis. Neurochem Int.Google Scholar
  29. 29.
    Crespo, E., M. Macías, D. Pozo, G. Escames, M. Martín, F. Vives, J.M. Guerrero, and D. Acuña-Castroviejo. 1999. Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. The FASEB Journal 13 (12): 1537–1546.CrossRefPubMedGoogle Scholar
  30. 30.
    Alzoubi, K.H., F.A. Mayyas, O.F. Khabour, F.M. Bani Salama, F.H. Alhashimi, and N.M. Mhaidat. 2016. Chronic melatonin treatment prevents memory impairment induced by chronic sleep deprivation. Molecular Neurobiology 53 (5): 3439–3447.CrossRefPubMedGoogle Scholar
  31. 31.
    Srinivasan, V., S.R. Pandi-Perumal, D.W. Spence, H. Kato, and D.P. Cardinali. 2010. Melatonin in septic shock: Some recent concepts. Journal of Critical Care 25 (4): 656.e1–656.e6.CrossRefGoogle Scholar
  32. 32.
    Zhao, L., R. An, Y. Yang, X. Yang, H. Liu, L. Yue, X. Li, Y. Lin, R.J. Reiter, and Y. Qu. 2015. Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress: The role of SIRT1 signaling. Journal of Pineal Research 59 (2): 230–239.CrossRefPubMedGoogle Scholar
  33. 33.
    Guo, Y., J. Sun, T. Li, Q. Zhang, S. Bu, Q. Wang, and D. Lai. 2017. Melatonin ameliorates restraint stress-induced oxidative stress and apoptosis in testicular cells via NF-κB/iNOS and Nrf2/ HO-1 signaling pathway. Scientific Reports 7 (1): 9599.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Alamili, M., K. Bendtzen, J. Lykkesfeldt, J. Rosenberg, and I. Gögenur. 2014. Melatonin suppresses markers of inflammation and oxidative damage in a human daytime endotoxemia model. Journal of Critical Care 29 (1): 184.e9–184184.CrossRefGoogle Scholar
  35. 35.
    Wang YS, Li YY, Cui W, Li LB, Zhang ZC, Tian BP, Zhang GS. 2017. Melatonin attenuates pain hypersensitivity and decreases astrocyte-mediated spinal neuroinflammation in a rat model of oxaliplatin-induced pain. Inflammation.  https://doi.org/10.1007/s10753-017-0645-y.
  36. 36.
    Ozer, E.K., M.T. Goktas, I. Kilinc, S. Pehlivan, H. Bariskaner, C. Ugurluoglu, and A.B. Iskit. 2017. Coenzyme Q10 improves the survival, mesenteric perfusion, organs and vessel functions in septic rats. Biomedicine & Pharmacotherapy 91: 912–919.CrossRefGoogle Scholar
  37. 37.
    Li, M., L. Yong-Zhe, M. Ya-Qun, Z. Sheng-Suo, Z. Li-Tao, and P. Ning-Ling. 2013. Ulinastatin alleviates neuroinflammation but fails to improve cognitive function in aged rats following partial hepatectomy. Neurochemical Research 38 (5): 1070–1077.CrossRefPubMedGoogle Scholar
  38. 38.
    Shukla M, Boontem P, Reiter RJ, Satayavivad J, Govitrapong P. 2017. Mechanisms of melatonin in alleviating Alzheimer’s disease. Curr Neuropharmacol.Google Scholar
  39. 39.
    Hung, M.W., G.L. Tipoe, A.M. Poon, R.J. Reiter, and M.L. Fung. 2008. Protective effect of melatonin against hippocampal injury of rats with intermittent hypoxia. Journal of Pineal Research 44 (2): 214–221.CrossRefPubMedGoogle Scholar
  40. 40.
    Ozacmak, V.H., F. Barut, and H.S. Ozacmak. 2009. Melatonin provides neuroprotection by reducing oxidative stress and HSP70 expression during chronic cerebral hypoperfusion in ovariectomized rats. Journal of Pineal Research 47 (2): 156–163.CrossRefPubMedGoogle Scholar
  41. 41.
    Blair, M.G., N.N. Nguyen, S.H. Albani, M.M. L'Etoile, M.M. Andrawis, L.M. Owen, R.F. Oliveira, M.W. Johnson, and D.L. Purvis. 2013. Developmental changes in structural and functional properties of hippocampal AMPARs parallels the emergence of deliberative spatial navigation in juvenile rats. The Journal of Neuroscience 33 (30): 12218–12228.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Danzer, S.C., R.J. Kotloski, C. Walter, M. Hughes, and J.O. McNamara. 2008. Altered morphology of hippocampal dentate granule cell presynaptic and postsynaptic terminals following conditional deletion of TrkB. Hippocampus 18 (7): 668–678.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Hopkins, M.E., and D.J. Bucci. 2010. BDNF expression in perirhinal cortex is associated with exercise-induced improvement in object recognition memory. Neurobiology of Learning and Memory 94 (2): 278–284.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Gui, L., X. Lei, and Z. Zuo. 2017. Decrease of glial cell-derived neurotrophic factor contributes to anesthesia- and surgery-induced learning and memory dysfunction in neonatal rats. J Mol Med (Berl) 95 (4): 369–379.CrossRefGoogle Scholar
  45. 45.
    Rudnitskaya, E.A., K.Y. Maksimova, N.A. Muraleva, S.V. Logvinov, L.V. Yanshole, N.G. Kolosova, and N.A. Stefanova. 2015. Beneficial effects of melatonin in a rat model of sporadic Alzheimer’s disease. Biogerontology 16 (3): 303–316.CrossRefPubMedGoogle Scholar
  46. 46.
    Li, Z., X. Li, M.T.V. Chan, W.K.K. Wu, D. Tan, and J. Shen. 2017. Melatonin antagonizes interleukin-18-mediated inhibition on neural stem cell proliferation and differentiation. Journal of Cellular and Molecular Medicine 21 (9): 2163–2171.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Manda, K., M. Ueno, and K. Anzai. 2009. Cranial irradiation-induced inhibition of neurogenesis in hippocampal dentate gyrus of adult mice: Attenuation by melatonin pretreatment. Journal of Pineal Research 46 (1): 71–78.CrossRefPubMedGoogle Scholar
  48. 48.
    Kilic, E., U. Kilic, M. Bacigaluppi, Z. Guo, N.B. Abdallah, D.P. Wolfer, R.J. Reiter, D.M. Hermann, and C.L. Bassetti. 2008. Delayed melatonin administration promotes neuronal survival, neurogenesis and motor recovery, and attenuates hyperactivity and anxiety after mild focal cerebral ischemia in mice. Journal of Pineal Research 45 (2): 142–148.CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  • Mu-huo Ji
    • 1
  • De-guo Xia
    • 2
  • Lan-yue Zhu
    • 3
  • Xia Zhu
    • 1
  • Xiao-yan Zhou
    • 1
  • Jiang-yan Xia
    • 3
  • Jian-jun Yang
    • 1
  1. 1.Department of AnesthesiologyJinling Clinical Medical College of Nanjing Medical UniversityNanjingChina
  2. 2.Department of AnesthesiologyClinical Medical College of Yangzhou University (Subei People’s Hospital of Jiangsu Province)YangzhouChina
  3. 3.Department of Anesthesiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina

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