Skip to main content

Advertisement

Log in

Does Melatonin Ameliorate Neurological Changes Associated With Alzheimer’s Disease in Ovariectomized Rat Model?

  • Original Article
  • Published:
Indian Journal of Clinical Biochemistry Aims and scope Submit manuscript

Abstract

This study aimed to elucidate the mechanisms of melatonin to manage neurological damage in Alzheimer’s disease (AD) induced in ovariectomized rats. Forty adult female rats were enrolled in our study and were classified as; gonad intact control, ovariectomized control group, ovariectomized rats received melatonin, ovariectomized rats injected with AlCl3 to induce AD and AD-induced rats treated with melatonin. Hydrogen peroxide (H2O2), malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), B cell lymphoma 2 (Bcl-2), brain derived neurotrophic factor (BDNF), acetylcholinesterase (AchE) and acetylcholine (Ach) were estimated in the brain tissues of the different groups. Treatment of AD-induced rats with melatonin produced marked improvement in the most studied biomarkers which was confirmed by histological investigation of the brain. In Conclusion, melatonin significantly ameliorates the neurodegeneration characteristic of AD in experimental animal model due to its antioxidant, antiapoptotic, neurotrophic and anti-amyloidogenic activities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Welsh-Bohmer KA, White CL. Alzheimer’s disease: what changes in the brain cause dementia? Neurology. 2009;72:21–3.

    Article  Google Scholar 

  2. Smith MA, Wehr K, Harris PL, Siedlak SL, Connor JR, Perry G. Abnormal localization of iron regulatory protein in Alzheimer’s disease. Brain Res. 1998;788:232–6.

    Article  PubMed  CAS  Google Scholar 

  3. Walton JR, Wang MX. APP expression, distribution and accumulation are altered by aluminum in a rodent model for Alzheimer’s disease. J Inorg Biochem. 2009;103:1548–54.

    Article  PubMed  CAS  Google Scholar 

  4. Gillies GE, McArthur S. Estrogen actions in the brain and the basis for differential action in men and women: a case for sex specific medicines. Pharmacol Rev. 2010;62:155–98.

    Article  PubMed  CAS  Google Scholar 

  5. Garcia T, Esparza JL, Nogues MR, Romeu M, Domingo JL, Gomez M. Oxidative stress status and RNA expression in hippocampus of an animal model of Alzheimer’s disease after chronic exposure to aluminum. Hippocampus. 2010;20:218–25.

    PubMed  CAS  Google Scholar 

  6. Yang X, Yang Y, Fu Z, Li Y, Feng J, Luo J, et al. Melatonin ameliorates Alzheimer like pathological changes and spatial memory retention impairment induced by calyculin A. J Psychopharmacol. 2011;25(8):1118–25.

    Article  PubMed  CAS  Google Scholar 

  7. AOAC. Official Methods of Analysis. 16th ed. Association of Official Analysis: Washington; 1995.

  8. Agrawal RE, Tyagi R, Shukla R, Nath C. Effect of insulin and melatonin on acetylcholinesterase activity in the brain of amnesic mice. Behav Brain Res. 2008;189:381–6.

    Article  PubMed  CAS  Google Scholar 

  9. Julka D, Gill KD. Effect of aluminum on regional brain antioxidant defense status in Wistar rats. Res Exp Med. 1996;196:187–94.

    CAS  Google Scholar 

  10. Tsakiris S, Schulpis KH, Marinou K, Behrakis P. Protective effect of l-cysteine and glutathione on the modulated suckling rat brain Na+, K+-ATPase and Mg2+-ATPase activities induced by the in vitro galactosaemia. Pharmacol Res. 2004;49:475–9.

    Article  PubMed  CAS  Google Scholar 

  11. Aebi H. Catalase in vitro. Meth Enzymol. 1984;105:121–6.

    Article  PubMed  CAS  Google Scholar 

  12. Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta. 1978;90:37–43.

    Article  PubMed  CAS  Google Scholar 

  13. Koracevic DG, Koracevic G, Djordjevic V, Andrejevic S, Cosic V. Method for the measurement of antioxidant activity in human fluids. J Clin Pathol. 2001;54:356–61.

    Article  PubMed  CAS  Google Scholar 

  14. Nishikimi M, Rao NA, Yagi K. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun. 1972;46:849–54.

    Article  PubMed  CAS  Google Scholar 

  15. Barbareschi M, Caffo O, Veronese S, Leek RD, Fina P, Fox S, et al. Bcl-2 and P53 expression in node negative breast carcinoma-a study with long term follow up. Human Pathol. 1996;27:1149–55.

    Article  CAS  Google Scholar 

  16. Barakat-Walter I. Brain derived neurotrophic factor like immunoreactivity is localized mainly in small sensory neurons of rat dorsal root ganglia. J Neurosci Meth. 1996;68:281–8.

    Article  CAS  Google Scholar 

  17. Den Blaauwen DH, Poppe WA, Tritschler W. Acetylcholinesterase with acetylthiocholine iodide as substrate: references depending on age and sex with special reference to hormonal effects and pregnancy. J Clin Chem Clin Biochem. 1983;21:381–6.

    Google Scholar 

  18. Oswald C, Smits SH, Hoing M, Sohn-Bosser L, Dupont L, Le Rudulier D, et al. Crystal structures of choline/acetylcholine substrate-binding protein chox from sinorhizobium meliloti in the liganded and unliganded-closed states. J Biol Chem. 2008;283:32848–59.

    Article  PubMed  CAS  Google Scholar 

  19. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem. 1951;193:265–75.

    PubMed  CAS  Google Scholar 

  20. Carleton HM, Drury RAB, Wallington EA. Carleton’s histological technique. 5th ed. New York: Oxford University Press, Oxford; 1980. pp. 188–189, 237–240, 290–291.

  21. Armitage P, Berry G. Comparison of several groups. In: Armitage P, Berry G, editors. Statistical method in medical research, 2th ed. Oxford: Blackwell Significant Publication; 1987. pp. 186–213.

  22. Bharathi P, Vasudevaraju P, Govindaraju M, Palanisamy AP, Sambamurti K, Rao KS. Molecular toxicity of aluminum in relation to neurodegeneration. Ind J Med Res. 2008;128:545–56.

    CAS  Google Scholar 

  23. Tuneva J, Chittur S, Boldyrev AA, Birman I, Carpenter DO. Cerebellar granule cell death induced by aluminum. Neurotoxicol Res. 2006;9:297–304.

    Article  CAS  Google Scholar 

  24. Kumar V, Bal A, Gill KD. Impairment of mitochondrial energy metabolism in different regions of rat brain following chronic exposure to aluminum. Brain Res. 2008;1232:94–103.

    Article  PubMed  CAS  Google Scholar 

  25. Kumar V, Bal A, Gill KD. Susceptibility of mitochondrial superoxide dismutase to aluminum-induced oxidative damage. Toxicology. 2009;255:117–23.

    Article  PubMed  CAS  Google Scholar 

  26. Huh JW, Choi MM, Lee JH, Yang SJ, Kim MJ, Choi J, et al. Activation of monoamine oxidase isotypes by prolonged intake of aluminum in rat brain. J Inorg Biochem. 2005;99:2088–91.

    Article  PubMed  CAS  Google Scholar 

  27. Tripathi S, Mahdia AA, Nawaba A, Chandera R, Hasan M, Siddiqui MS, et al. Influence of age on aluminum-induced lipid peroxidation and neurolipofuscin in frontal cortex of rat brain: a behavioral, biochemical and ultrastructural study. Brain Res. 2009;1253:107–16.

    Article  PubMed  CAS  Google Scholar 

  28. Martinez GR, Almeida EA, Klitzke CF, Onuki J, Prado FM, Medeiros MH, Di Mascio P. Measurement of melatonin and its metabolites: importance for the evaluation of their biological roles. Endocrine. 2005;27:111–8.

    Article  PubMed  CAS  Google Scholar 

  29. Sharman EH, Bondy SC, Sharman KG, Lahiri D, Cotman CW, Perreau VM. Effects of melatonin and age on gene expression in mouse CNS using microarray analysis. Neurochem Int. 2007;50:336–44.

    Article  PubMed  CAS  Google Scholar 

  30. Allegra M, Reiter RJ, Tan DX, Gentile C, Tesoriere L, Livrea MA. Melatonin’s interaction with reactive species. J Pineal Res. 2003;34:1–10.

    Article  PubMed  CAS  Google Scholar 

  31. Gulcin I, Buyukokuroglu M, Kufrevioglu OI. Metals chelating and hydrogen peroxide scavenging effects of melatonin. J Pineal Res. 2003;34:278–81.

    Article  PubMed  CAS  Google Scholar 

  32. Albendea CD, Gomez-Trullen EM, Fuentes-Broto L, Miana-Mena FJ, Millan-Plano S, Reyes-Gonzales MC, et al. Melatonin reduces lipid and protein oxidative damage in synaptosomes due to aluminum. J Trace Elem Med Biol. 2007;21:261–8.

    Article  PubMed  CAS  Google Scholar 

  33. Mayo JC, Tan DX, Sainz RM, Lopez-Burillo S, Reiter RJ. Oxidative damage to catalase-induced by peroxyl radicals: functional protection by melatonin and other antioxidants. Free Radic Res. 2003;37:543–53.

    Article  PubMed  CAS  Google Scholar 

  34. Munoz-Castaneda JR, Muntane J, Munoz MC, Bujalance I, Montilla P, Tunez I. Estradiol and catecholestrogens protect against adriamycin-induced oxidative stress in erythrocytes of ovariectomized rats. Toxicol Lett. 2006;160:196–203.

    Article  PubMed  CAS  Google Scholar 

  35. Kumar V, Bal A, Gill KD. Aluminum-induced oxidative DNA damage recognition and cell cycle disruption in different regions of rat brain. Toxicology. 2009;264:137–44.

    Article  PubMed  CAS  Google Scholar 

  36. Nehru B, Anand P. Oxidative damage following chronic aluminum exposure in adult and pup rat brains. J Trace Elem Med Biol. 2005;19:203–8.

    Article  PubMed  CAS  Google Scholar 

  37. Reiter RJ, Tan DX, Burkhardt S. Reactive oxygen and nitrogen species and cellular and organismal decline: amelioration with melatonin. Mech Aging Dev. 2002;123:1007–19.

    Article  PubMed  CAS  Google Scholar 

  38. Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res. 2004;36:1–9.

    Article  PubMed  CAS  Google Scholar 

  39. Gomez M, Esparza JL, Nogues MR, Giralt M, Cabre M, Domingo JL. Prooxidant activity of aluminum in the rat hippocampus: gene expression of antioxidant enzymes after melatonin administration. Free Radic Biol Med. 2005;38:104–11.

    Article  PubMed  CAS  Google Scholar 

  40. Sharma K, Mehra RD. Long term administration of estrogen or tamoxifen to ovariectomized rats affords neuroprotection to hippocampal neurons by modulating the expression of Bcl-2 and Bax. Brain Res. 2008;1204:1–15.

    Article  PubMed  CAS  Google Scholar 

  41. Johnson VJ, Kim S, Sharma RP. Aluminum maltolate induces apoptosis and necrosis in neuro-2a cells: potential role for p53 signaling. Toxicol Sci. 2005;83:329–39.

    Article  PubMed  CAS  Google Scholar 

  42. Takuma K, Matsuo A, Himeno Y, Hoshina Y, Ohno Y, Funatsu Y, et al. 17-β estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats. Neuroscience. 2007;146:60–8.

    Article  PubMed  CAS  Google Scholar 

  43. Nagatsu T, Mogi M, Ichinose H, Togari A. Changes in cytokines and neurotrophins in Parkinson’s disease. J Neural Transm. 2000;2000:277–90.

    Google Scholar 

  44. Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron. 1998;20:709–26.

    Article  PubMed  CAS  Google Scholar 

  45. Luchetti F, Betti M, Canonico B, Arcangeletti M, Ferri P, Galli F, Papa S. ERK/MAPK activation mediates the antiapoptotic signaling of melatonin in UVB-stressed U937 cells. Free Radic Biol Med. 2009;46:339–51.

    Article  PubMed  CAS  Google Scholar 

  46. Imbesi M, Uz T, Manev H. Melatonin receptor agonist ramelteon activates the extracellular signal regulated kinase 1/2 in mouse cerebellar granule cells. Neuroscience. 2008;155:1160–4.

    Article  PubMed  CAS  Google Scholar 

  47. Gulya K, Rakonczay Z, Kasa P. Cholinotoxic effects of aluminum in rat brain. J Neurochem. 1990;54:1020–6.

    Article  PubMed  CAS  Google Scholar 

  48. Zhang J, Yang JQ, He BC, Zhou QX, Yu HR, Tang Y, Liu BZ. Berberine and total base from rhizoma coptis chinensis attenuate brain injury in an aluminum-induced rat model of neurodegenerative disease. Saud Med J. 2009;30:760–6.

    Google Scholar 

  49. Kaizer RR, Correa MC, Gris LR, Da Rosa CS, Bohrer D, Morsch VM, et al. Effect of long term exposure to aluminum on the acetylcholinesterase activity in the central nervous system and erythrocytes. Neurochem Res. 2008;33:2294–301.

    Article  PubMed  CAS  Google Scholar 

  50. Alleva K, Rankin J, Santucci D. Neurobehavioural alteration in rodents following developmental exposure to aluminum. Toxicol Ind Health. 1998;14:209–21.

    Article  PubMed  CAS  Google Scholar 

  51. Iwasaki K, Al-Khatib IH, Egashira N, Akiyoshi Y, Arai T, Mishima K, et al. Ovariectomy combined with amyloid-β1-42 impairs memory by decreasing acetylcholine release and α7nAchR expression without induction of apoptosis in the hippocampus CA1 neurons of rats. Neurotox Res. 2004;6:299–309.

    Article  PubMed  Google Scholar 

  52. Weinstock M, Shoham S. Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity. J Neural Transm. 2004;111:347–66.

    Article  PubMed  CAS  Google Scholar 

  53. Hua X, Lei M, Zhang Y, Ding J, Han Q, Hu G, Xiao M. Long term d-galactose injection combined with ovariectomy serves as a new rodent model for Alzheimer’s disease. Life Sci. 2007;80:1897–905.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hanaa H. Ahmed.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ahmed, H.H., Estefan, S.F., Mohamd, E.M. et al. Does Melatonin Ameliorate Neurological Changes Associated With Alzheimer’s Disease in Ovariectomized Rat Model?. Ind J Clin Biochem 28, 381–389 (2013). https://doi.org/10.1007/s12291-012-0284-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12291-012-0284-x

Keywords

Navigation