Melatonin Delays Brain Aging by Decreasing the Nitric Oxide Level

Aging is believed to be a first-order risk factor for most neurodegenerative disorders. The neuronal cell loss that occurs with aging has been partly attributed to increased production of nitric oxide and high caspase activity. Melatonin (MLT) might have a role in the regulation of nitric oxide in the brain. We investigated the effects of MLT on the nitrite/nitrate levels and caspase-3 enzyme activity in the frontal cortex, temporal cortex, and hippocampus of young and aged rats. There was no significant difference between the nitrite levels in the frontal cortex and hippocampus of young and aged animals. In the temporal cortex of aged rats, the nitrite level, however, was significantly higher (P < 0.001). In the aged group, MLT significantly decreased these levels in the brain regions. Caspase-3 enzyme activity in the temporal and frontal cortices was significantly higher in aged rats when compared to the control group (P < 0.05). Melatonin did not cause significant changes in caspase-3 activity in any brain region of both young and aged rats. Thus, brain regions demonstrate different caspase-3 enzyme activities and nitrite levels in the aging process. Exogenous MLT administration might delay brain aging (by moderation of death of neurons and glia) via decreasing the nitrite/nitrate level.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    R. A. Floyd and K. Hensley, “Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases,” Neurobiol. Aging, 23, No. 5, 795–807 (2002).

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    X. H. Deng, G. Bertini, Y. Z. Xu, et al., “Cytokineinduced activation of glial cells in the mouse brain is enhanced at an advanced age,” Neuroscience, 141, No. 2, 645–661 (2006).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    I. Rozovsky, C. E. Finch, and T. E. Morgan, “Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation,” Neurobiol. Aging, 19, No. 1, 97–103 (1998).

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    R. E. Mrak and W. S. Griffin, “Glia and their cytokines in progression of neurodegeneration,” Neurobiol. Aging, 26, No. 3, 349–354 (2005).

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    M. P. Mattson, “Apoptosis in neurodegenerative disorders,” Nat. Rev. Mol. Cell. Biol., 1, No. 2, 120–129 (2000).

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    M. P. Mattson, “Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders,” Antioxid. Redox Signal., 8, Nos. 11/12, 1997–2006 (2006).

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    R. M. Friedlander, “Apoptosis and caspases in neurodegenerative diseases,” New Engl. J. Med., 348, No. 14, 1365–1375 (2003).

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    C. M. Troy and G. S. Salvesen, “Caspases in the brain,” J. Neurosci. Res., 69, No. 2, 145–150 (2002).

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    S. M. McCann, “The nitric oxide hypothesis of brain aging,” Exp. Gerontol., 32, Nos. 4/5, 431–440 (1997).

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    A. Navarro and A. Boveris, “Mitochondrial nitric oxide synthase, mitochondrial brain dysfunction in aging, and mitochondria-targeted antioxidants,” Adv. Drug. Deliv. Rev., 60, 1534–1544 (2008).

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    P. K. Kim, Y. G. Kwon, H. T. Chung, and Y. M. Kim, “Regulation of caspases by nitric oxide,” Ann. New York Acad. Sci., 962, 42–52 (2002).

    Article  CAS  Google Scholar 

  12. 12.

    J. Sastre, F. V. Pallardó, and J. Viña, “Mitochondrial oxidative stress plays a key role in aging and apoptosis,” IUBMB Life, 49, No. 5, 427–435 (2000).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    M. E. Götz, E. Ahlbom, B. Zhivotovsky, et al., “Radical scavenging compound J 811 inhibits hydrogen peroxideinduced death of cerebellar granule cells,” J. Neurosci. Res., 56, No. 4, 420–426 (1999).

    PubMed  Article  Google Scholar 

  14. 14.

    A. M. Stranahan and M. P. Mattson, “Recruiting adaptive cellular stress responses for successful brain ageing,” Nat. Rev. Neurosci., 13, No. 3, 209–216 (2012).

    PubMed  CAS  Google Scholar 

  15. 15.

    M. Tajes Orduña, C. Pelegrí Gabalda, J. Vilaplana Hortensi, et al., “An evaluation of the neuroprotective effects of melatonin in an in vitro experimental model of age-induced neuronal apoptosis,” J. Pineal Res., 46, No. 3, 262–267 (2009).

    PubMed  Article  Google Scholar 

  16. 16.

    Y. Hong, K. J. Palaksha, K. Park, et al., “Melatonin plus exercise-based neurorehabilitative therapy for spinal cord injury,” J. Pineal Res., 49, No. 3, 201–209 (2010).

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    A. Leja-Szpak, J. Jaworek, P. Pierzchalski, and R. J. Reiter, “Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1),” J. Pineal Res., 49, No. 3, 248–255 (2010).

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    R. Hardeland, D. X. Tan, and R. J. Reiter, “Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines,” J. Pineal Res., 47, No. 2, 109–126 (2009).

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    K. G. Akbulut, B. Gonul, and H. Akbulut, “Exogenous melatonin decreases age-induced lipid peroxidation in the brain,” Brain Res., 1238, 31–35 (2008).

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    A. R. Meki, D. Esmail Eel, A. A. Hussein, and H. M. Hassanein, “Caspase-3 and heat shock protein-70 in rat liver treated with aflatoxin B1: effect of melatonin,” Toxicon, 43, No. 1, 93–100 (2004).

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    L. Casciola-Rosen, D. W. Nicholson, T. Chong, et al., “Apopain/CPP32 cleaves proteins that are essential for cellular repair: a fundamental principle of apoptotic death,” J. Exp. Med., 183, No. 5, 1957–1964 (1996).

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    K. M. Miranda, M. G. Espey, and D. A. Wink, “A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite,” Nitric Oxide, 5, No. 1, 62–71 (2001).

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    A. M. Lynch and M. A. Lynch, “The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation,” Eur. J. Neurosci., 15, No. 11, 1779–1788 (2002).

    PubMed  Article  Google Scholar 

  24. 24.

    M. K. Lucin and T. Wyss-Coray, “Immune activation in brain aging and neurodegeneration: too much or too little?” Neuron, 64, No. 1, 110–122 (2009).

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    G. E. Landreth, “Microglia in central nervous system diseases,” J. Neuroimmune Pharmacol., 4, No. 4, 369–370 (2009).

    PubMed  Article  Google Scholar 

  26. 26.

    J. P. Godbout and R. W. Johnson, “Age and neuroinflammation: a lifetime of psychoneuroimmune consequences,” Immunol. Allergy Clin. North Am., 29, No. 2, 321–337 (2009).

    PubMed  Article  Google Scholar 

  27. 27.

    E. Siles, E. Martínez-Lara, A. Cañuelo, et al., “Agerelated changes of the nitric oxide system in the rat brain,” Brain Res., 956, No. 2, 385–392 (2002).

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    A. Law, S. Doré, S. Blackshaw, et al., “Alteration of expression levels of neuronal nitric oxide synthase and haem oxygenase-2 messenger RNA in the hippocampi and cortices of young adult and aged cognitively unimpaired and impaired Long-Evans rats,” Neuroscience, 100, No. 4, 769–775 (2000).

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    D. Vernet, J. J. Bonavera, R. S. Swerdloff, et al., “Spontaneous expression of inducible nitric oxide synthase in the hypothalamus and other brain regions of aging rats,” Endocrinology, 139, No. 7, 3254–3261 (1998).

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    P. Liu, Y. Jing, and H. Zhang, “Age-related changes in arginine and its metabolites in memory-associated brain structures,” Neuroscience, 164, No. 2, 611–628 (2009).

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    S. Blanco, F. J. Molina, L. Castro, et al., “Study of the nitric oxide system in the rat cerebellum during aging,” BMC Neurosci., 11, 78 (2010).

    PubMed  Article  Google Scholar 

  32. 32.

    C. Hutton, B. Draganski, J. Ashburner, and N. Weiskopf, “A comparison between voxel-based cortical thickness and voxel-based morphometry in normal aging,” Neuroimage, 48, No. 2, 371–380 (2009).

    PubMed  Article  Google Scholar 

  33. 33.

    A. Schuitemaker, T. F. van der Doef, R. Boellaard, et al., “Microglial activation in healthy aging,” Neurobiol. Aging, 33, No. 6, 1067–1072 (2012).

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    X. G. Luo, J. Q. Ding, and S. D. Chen, “Microglia in the aging brain: relevance to neurodegeneration,” Mol. Neurodegener., 5, 12 (2010).

    PubMed  Article  Google Scholar 

  35. 35.

    A. Das, A. Belagodu, R. J. Reiter, et al., “Cytoprotective effects of melatonin on C6 astroglial cells exposed to glutamate excitotoxicity and oxidative stress,” J. Pineal Res., 45, No. 2, 117–124 (2008).

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    K. G. Akbulut, H. Akbulut, N. Akgun, and B. Gonul, “Melatonin decreases apoptosis in gastric mucosa during aging,” Aging Clin. Exp. Res., 24, No. 1, 15–20 (2012).

    PubMed  CAS  Google Scholar 

  37. 37.

    Y. Zhang, E. Chong, and B. Herman, “Age-associated increases in the activity of multiple caspases in Fisher 344 rat organs,” Exp. Gerontol., 37, No. 6, 777–789 (2002).

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    A. Zhang, D. E. Lorke, S. X. Wu, and D.T. Yew, “Caspase-3 immunoreactivity in different cortical areas of young and aging macaque (Macaca mulatta) monkeys,” Neurosignals, 15, No. 2, 64–73 (2007).

    Article  Google Scholar 

  39. 39.

    J. Chetsawang, P. Govitrapong, and B. Chetsawang, “Melatonin inhibits MPP+-induced caspase-mediated death pathway and DNA fragmentation factor-45 cleavage in SK-N-SH cultured cells,” J. Pineal Res., 43, No. 2, 115–120 (2007).

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to K. G. Akbulut.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Akbulut, K.G., Guney, S., Cetin, F. et al. Melatonin Delays Brain Aging by Decreasing the Nitric Oxide Level. Neurophysiology 45, 187–192 (2013). https://doi.org/10.1007/s11062-013-9368-3

Download citation

Keywords

  • aging
  • caspase-3
  • melatonin
  • nitric oxide
  • temporal cortex
  • frontal cortex
  • hippocampus