Advertisement

Biogerontology

, Volume 16, Issue 3, pp 303–316 | Cite as

Beneficial effects of melatonin in a rat model of sporadic Alzheimer’s disease

  • Ekaterina A. Rudnitskaya
  • Kseniya Yi. Maksimova
  • Natalia A. Muraleva
  • Sergey V. Logvinov
  • Lyudmila V. Yanshole
  • Nataliya G. Kolosova
  • Natalia A. StefanovaEmail author
Research Article

Abstract

Melatonin synthesis is disordered in patients with Alzheimer’s disease (AD). To determine the role of melatonin in the pathogenesis of AD, suitable animal models are needed. The OXYS rats are an experimental model of accelerated senescence that has also been proposed as a spontaneous rat model of AD-like pathology. In the present study, we demonstrate that disturbances in melatonin secretion occur in OXYS rats at 4 months of age. These disturbances occur simultaneously with manifestation of behavioral abnormalities against the background of neurodegeneration and alterations in hormonal status but before the signs of amyloid-β accumulation. We examined whether oral administration of melatonin could normalize the melatonin secretion and have beneficial effects on OXYS rats before progression to AD-like pathology. The results showed that melatonin treatment restored melatonin secretion in the pineal gland of OXYS rats as well as the serum levels of growth hormone and IGF-1, the level of BDNF in the hippocampus and the healthy state of hippocampal neurons. Additionally, melatonin treatment of OXYS rats prevented an increase in anxiety and the decline of locomotor activity, of exploratory activity, and of reference memory. Thus, melatonin may be involved in AD progression, whereas oral administration of melatonin could be a prophylactic strategy to prevent or slow down the progression of some features of AD pathology.

Keywords

Alzheimer’s disease Melatonin Neurodegeneration OXYS rats 

Notes

Acknowledgments

We thank Dr. Vadim V. Yanshole of the International Tomography Center SB RAS, for assistance with the liquid chromatography with mass spectrometry experiments. This work was supported by a grant from the Russian Foundation for Basic Research (project # 12-04-00091) and partially by grants from the government of the Russian Federation # 2012-220-03-435 and # 14.B25.31.0033. The mass spectrometric analysis involved financial support by the Russian Scientific Foundation (project # 14-14-00056).

Conflict of interest

The authors declare that they have no competing financial interests.

References

  1. Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Therapeut 138:155–175CrossRefGoogle Scholar
  2. Andersen P, Morris R, Amaral D, Bliss T, O’Kneefe J (2007) The Hippocampus Book. Oxford University Press, Inc., New YorkGoogle Scholar
  3. Bubenik GA, Konturek SJ (2011) Melatonin and aging: prospects for human treatment. J Physiol Pharmacol 62:13–19PubMedGoogle Scholar
  4. Castellano JM, Deane R, Gottesdiener AJ, Verghese PhB, Stewart FR, West T, Paoletti AC, Kasper TR, DeMattos RB, Zlokovic BV, Holtzman DM (2012) Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis. Proc Natl Acad Sci USA 109:15502–15507CrossRefPubMedCentralPubMedGoogle Scholar
  5. Durany N, Michel T, Kurt J, Cruz-Sánchez FF, Cervás-Navarro J, Reiderer P (2000) Brain-derived neurotrophic factor and neurotrophin-3 levels in Alzheimer’s disease brains. Int J Dev Neurosci 18:807–813CrossRefGoogle Scholar
  6. Esposito E, Cuzzocrea S (2010) Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol 8:228–242CrossRefPubMedCentralPubMedGoogle Scholar
  7. Hardeland R (2012) Melatonin in aging and disease—multiple consequences of reduced secretion, options and limits of treatment. Aging Dis 3:194–225PubMedCentralPubMedGoogle Scholar
  8. Jenwitheesuk A, Nopparat C, Mukda S, Wongchitrat P, Govitrapong P (2014) Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways. Int J Mol Sci 15:16848–16884CrossRefPubMedCentralPubMedGoogle Scholar
  9. Kolosova NG, Stefanova NA, Muraleva NA, Skulachev VP (2012) The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats. Aging (Albany NY) 4:686–694Google Scholar
  10. Kozhevnikova OS, Korbolina EE, Stefanova NA, Muraleva NA, Orlov YL, Kolosova NG (2013) Association of AMD-like retinopathy development with an Alzheimer’s disease metabolic pathway in OXYS rats. Biogerontology 14:753–762CrossRefPubMedGoogle Scholar
  11. Lin L, Huang QX, Yang SS, Chu J, Wang JZ, Tian Q (2013) Melatonin in Alzheimer’s disease. Int J Mol Sci 14:14575–14593CrossRefPubMedCentralPubMedGoogle Scholar
  12. Moodly KK, Chan D (2014) The hippocampus in neurodegenerative disease. Front Neurol Neurosci 34:95–108CrossRefGoogle Scholar
  13. Nyberg F, Hallberg M (2013) Growth hormone and cognitive function. Nat Rev Endocrinol 9:357–365CrossRefPubMedGoogle Scholar
  14. Paxinos G, Watson CH (2007) The rat brain in stereotaxic coordinates, 6th edn. Elsevier, SydneyGoogle Scholar
  15. Ramírez-Rodríguez G, Klempin F, Babu H, Benítez-King G, Kempermann G (2009) Melatonin modulates cell survival of new neurons in the hippocampus of adult mice. Neuropsychopharmacology 34:2180–2191CrossRefPubMedGoogle Scholar
  16. Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361:1545–1564CrossRefPubMedCentralPubMedGoogle Scholar
  17. Sardi F, Fassina L, Venturini L, Inguscio M, Guerriero F, Rolfo E, Ricevuti G (2011) Alzheimer’s disease, autoimmunity and inflammation. The good, the bad and the ugly. Autoimmun Rev 11:149–153CrossRefPubMedGoogle Scholar
  18. Shcheglova TV, Amstislavskaya TG, Kolosova NG (2002) Serotonin metabolism in the brain structures of prematurely ageing OXYS rats. Neurochemistry 19:269–273Google Scholar
  19. Snytnikova OA, Tsentalovich YP, Stefanova NA, Fursova AZh, Kaptein R, Sagdeev RZ, Kolosova NG (2012) The therapeutic effect of mitochondria-targeted antioxidant SkQ1 and Cistanche deserticola is associated with increased levels of tryptophan and kynurenine in the rat lenses. Dokl Biochem Biophys 447:300–303CrossRefPubMedGoogle Scholar
  20. Stefanova NA, Fursova AZh, Kolosova NG (2010) Behavioral effects induced by mitochondria-targeted antioxidant SkQ1 in Wistar and senescence-accelerated OXYS rats. J Alzheimers Dis 21:479–491PubMedGoogle Scholar
  21. Stefanova NA, Fursova AZh, Sarsenbaev KN, Kolosova NG (2011) Effects of Cistanche deserticola on behavior and signs of cataract and retinopathy in senescence-accelerated OXYS rats. J Ethnopharmacol 138:624–632CrossRefPubMedGoogle Scholar
  22. Stefanova NA, Kozhevnikova OS, Vitovtov AO, Maksimova KYi, Logvinov SV, Rudnitskaya EA, Korbolina EE, Muraleva NA, Kolosova NG (2014a) Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease. Cell Cycle 13:1–12CrossRefGoogle Scholar
  23. Stefanova NA, Muraleva NA, Skulachev VP, Kolosova NG (2014b) Alzheimer’s disease-like pathology in senescence-accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1. J Alzheimers Dis 38:681–694PubMedGoogle Scholar
  24. Wu YH, Swaab DF (2007) Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer’s disease. Sleep Med 8:623–636CrossRefPubMedGoogle Scholar
  25. Yanshole VV, Snytnikova OA, Kiryutin AS, Yanshole LV, Sagdeev RZ, Tsentalovich YP (2014) Metabolomics of the rat lens: a combined LC–MS and NMR study. Exp Eye Res 125:71–78CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Ekaterina A. Rudnitskaya
    • 1
  • Kseniya Yi. Maksimova
    • 2
  • Natalia A. Muraleva
    • 1
  • Sergey V. Logvinov
    • 2
  • Lyudmila V. Yanshole
    • 3
    • 4
  • Nataliya G. Kolosova
    • 1
    • 4
    • 5
  • Natalia A. Stefanova
    • 1
    Email author
  1. 1.Institute of Cytology and GeneticsNovosibirskRussia
  2. 2.Siberian State Medical UniversityTomskRussia
  3. 3.International Tomography Center SB RASNovosibirskRussia
  4. 4.Novosibirsk State UniversityNovosibirskRussia
  5. 5.Institute of MitoengineeringMoscowRussia

Personalised recommendations