Skip to main content

Advertisement

SpringerLink
Log in

Anti-inflammatory effect of melatonin on Aβ vaccination in mice

  • Original Paper
  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Aβ vaccination as a therapeutic intervention of Alzheimer’s has many challenges, key among them is the regulation of inflammatory processes concomitant with excessive generation of free radicals seen during such interventions. Here we report the beneficial effects of melatonin on inflammation associated with Aβ vaccination in the central and peripheral nervous system of mice. Mice were divided into three groups (n = 8 in each): control, inflammation (IA), and melatonin-treated (IAM). The brain, liver, and spleen samples were collected after 5 days for quantitative assessment of plasma lipid peroxides (LPO), an oxidative stress marker, and antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (Gpx). IA group mice have shown the elevated concentration of LPO significantly while there was a reduction at antioxidant enzyme levels. In addition, a significant (P < 0.05) reduction in neurotransmitters like dopamine (DA), 5-hydroxytryptamine (5-HT), and norepinephrine (NE) was also observed in the IA group mice. Nevertheless, their metabolites, such as homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) increased significantly (P < 0.05) as compared to control. Samples were further evaluated at microscopic level to examine the neuropathological changes by immunohistochemical methods. Melatonin treatment effectively reversed these above changes and normalized the LPO and antioxidant enzyme levels (P < 0.05). Furthermore, melatonin salvaged the brain cells from inflammation. Our Immunohistochemical findings in the samples of melatonin-treated animals (IAM group) indicated diminished expression of glial fibrillary acidic protein (GFAP) and nuclear factor kappa B (NfκB) than those observed in the IA group samples. Our results suggest that administration of melatonin protects inflammation associated with Aβ vaccination, through its direct and indirect actions and it can be an effective adjuvant in the development of vaccination in immunotherapy for Alzheimer’s disease (AD).

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Butterfield DA, Perluigi M, Sultana R (2006) Oxidative stress in Alzheimer’s disease brain: new insights from redox proteomics. Eur J Pharmacol 545:39–50

    Article  PubMed  CAS  Google Scholar 

  2. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 5594:789–791

    Article  CAS  Google Scholar 

  3. Shastry BS (2003) Neurodegenerative disorders of protein aggregation. Neurochem Int 43:1–7

    Article  PubMed  CAS  Google Scholar 

  4. Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE (1998) Glial–neuronal interactions in Alzheimer’s disease: the potential role of a ‘cytokine cycle’ in disease progression. Brain Pathol 8:65–72

    Article  PubMed  CAS  Google Scholar 

  5. Benveniste EN, Nguyen VT, O’Keefe GM (2001) Immunological aspects of microglia: relevance to Alzheimer’s disease. Neurochem Int 39:381–391

    Article  PubMed  CAS  Google Scholar 

  6. Weiner H, Selkoe D (2002) Inflammation and therapeutic vaccination in CNS diseases. Nature 420:879–884

    Article  PubMed  CAS  Google Scholar 

  7. Check E (2002) Nerve inflammation halts trial for Alzheimer’s drug. Nature 415:462

    Article  PubMed  CAS  Google Scholar 

  8. Reiter RJ (1992) The ageing pineal gland and its physiological consequences. Bioessays 14:169–175

    Article  PubMed  CAS  Google Scholar 

  9. Reiter RJ (1998) Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol 56:359–384

    Article  PubMed  CAS  Google Scholar 

  10. Sutcu R, Yonden Z, Yilmaz A, Delibas N (2006) Melatonin increases NMDA receptor subunits 2A and 2B concentrations in rat hippocampus. Mol Cell Biochem 283:101–105

    Article  PubMed  CAS  Google Scholar 

  11. Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R (2006) Melatonin. FEBS J 273:2813–38

    Article  PubMed  CAS  Google Scholar 

  12. Raghavendra V, Singh V, Kulkarni SK, Agrewala JN (2001) Melatonin enhances Th2 cell mediated immune responses: lack of sensitivity to reversal by naltrexone or benzodiazepine receptor antagonists. Mol Cell Biochem 221:57–62

    Article  PubMed  CAS  Google Scholar 

  13. Lahari DK (1999) Melatonin affects the metabolism of the beta-amyloid precursor protein in different cell types. J␣Pineal Res 26:137–146

    Article  Google Scholar 

  14. Giovannelli L, Casamenti F, Scali C, Bartolini L, Pepeu G (1995) Differential effects of amyloid peptides beta-(1–40) and beta-(25–35) injections into the rat nucleus basalis. Neuroscience 66:781–792

    Article  PubMed  CAS  Google Scholar 

  15. Stepanichev MY, Zdobnova IM, Yakovlev AA, Onufriev MV, Lazareva NA, Zarubenko II, Gulyaeva NV (2003) Effects of tumor necrosis factor-alpha central administration on hippocampal damage in rat induced by amyloid beta-peptide (25–35). J Neurosci Res 71:110–120

    Article  PubMed  CAS  Google Scholar 

  16. Masilamoni JG, Jesudason EP, Baben B, Jebaraj CE, Dhandayuthapani S, Jayakumar R (2006) Molecular chaperone alpha-crystallin prevents detrimental effects of neuroinflammation. Biochim Biophys Acta 1762:284–293

    PubMed  CAS  Google Scholar 

  17. Jesudason EP, Masilamoni JG, Kirubagaran R, Davis GD, Jayakumar R (2005) The protective role of dl-alpha-lipoic acid in biogenic amines catabolism triggered by Abeta amyloid vaccination in mice. Brain Res Bull 65:361–367

    Article  PubMed  CAS  Google Scholar 

  18. Nielsen EH, Nybo M, Svehag SE (1999) Electron microscopy of prefibrillar structures and amyloid fibrils. Meth Enzymol 309:491–496

    Article  PubMed  CAS  Google Scholar 

  19. Thorsby E, Bratlie A (1970) A rapid method for preparation of pure lymphocyte suspensions. In: Terasaki PI (ed) Histocompatibility testing. Munksgaard Inc., Copenhagen, 1970, pp 655

  20. Klaunig JE, Goldblatt PJ, Hinton DE, Lipsky MM, Chacko J, Trump BF (1981) Mouse liver cell culture. I Hepatocyte isolation In Vitro 17:913–925

    PubMed  CAS  Google Scholar 

  21. Abe K, Saito H (1996) Menadione toxicity in cultured rat cortical astrocytes. Jpn J Pharmacol 72:299–306

    PubMed  CAS  Google Scholar 

  22. Pereira C, Santos MS, Oliveira C (1999) Involvement of oxidative stress on the impairment of energy metabolism induced by Aβ peptides on PC12 cells: protection by antioxidants. Neurobiol Dis 6:209–219

    Article  PubMed  CAS  Google Scholar 

  23. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  PubMed  CAS  Google Scholar 

  24. Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170–3175

    PubMed  CAS  Google Scholar 

  25. Beers RF, Seizer IW (1952) A spectroscopic method of for measuring breakdown of hydrogenperoxide by catalase. J Biol Chem 115:133–140

    Google Scholar 

  26. Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG (1973) Selenium: Biochemical role as a component of glutathione peroxidase. Science 179:588–590

    Article  PubMed  CAS  Google Scholar 

  27. Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione reductase and glutathione-S-transferase activities in rat lung and liver. Biochim Biophys Acta 582:67–70

    PubMed  CAS  Google Scholar 

  28. Bonting SL (1970) Sodium–potassium activated adenosine triphosphatase and cation transport. In: Bittar EE (ed) Membrane and ion transport, vol 1. London. Wiley interscience, pp 257–263

  29. Hjerten S, Pan H (1983) Purification and characterization of two forms of a low-affinity Ca2+-ATPase from erythrocyte membranes. Biochim Biophys Acta 728:281–288

    Article  PubMed  CAS  Google Scholar 

  30. Ohnishi T, Suzuki T, Suzuki Y, Ozawa KA (1982) Comparative study of plasma membrane Mg2+-ATPase activities in normal, regenerating and malignant cells. Biochim Biophys Acta 684:67–74

    Article  PubMed  CAS  Google Scholar 

  31. Fiske CH, Subbarao Y (1925) The colorimetric determination of phosphorus. J Biol Chem 66:375–400

    CAS  Google Scholar 

  32. Kim C, Speisky MB, Kharouba SN (1987) Rapid and sensitive method for measuring norepinephrine, dopamine, 5-hydroxytryptamine and their major metabolites in rat brain by high-performance liquid chromatography. Differential effect of probenecid, haloperidol and yohimbine on the concentrations of biogenic amines and metabolites in various regions of rat brain. J Chromatogr 386:25–35

    Article  PubMed  CAS  Google Scholar 

  33. Eng LF, Ghirnikar RS (1994) GFAP and astrogliosis. Brain Pathol 4:229–237

    PubMed  CAS  Google Scholar 

  34. Mason CA, Edmondson JC, Hatten ME (1988) The extending astroglial process: development of glial cell shape, the growing tip, and interactions with neurons. J Neurosci 8:3124–3134

    PubMed  CAS  Google Scholar 

  35. Tao-Cheng JH, Nagy Z, Brightman MW (1987) Tight junctions of brain endothelium in vitro are enhanced by astroglia. J Neurosci 7:3293–3299

    PubMed  CAS  Google Scholar 

  36. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherally administered antibodies against amyloid beta peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 8:916–919

    Article  CAS  Google Scholar 

  37. McGeer PL, McGeer EG (2004) Inflammation and the degenerative diseases of aging. Ann NY Acad Sci 1035: 104–16

    Article  PubMed  CAS  Google Scholar 

  38. Jesudason EP, Masilamoni JG, Jesudoss KS, Jayakumar R (2005) The protective role of dl-alpha-lipoic acid in the oxidative vulnerability triggered by Abeta-amyloid vaccination in mice. Mol Cell Biochem 270:29–37

    Article  PubMed  CAS  Google Scholar 

  39. Pappolla M, Bozner P,Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, Ghizo J (1998) Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem 273:7185–7188

    Article  PubMed  CAS  Google Scholar 

  40. Hynd MR, Scott HL, Dodd PR (2004) Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem Int 45:583–595

    Article  PubMed  CAS  Google Scholar 

  41. Reiter RJ (2000) Melatonin: lowering the high price of free radicals. News Physiol Sci 15:246–250

    PubMed  CAS  Google Scholar 

  42. Masilamoni JG, Jesudason EP, Jesudoss KS, Murali J, Paul SF, Jayakumar R (2005) Role of fibrillar Abeta25–35 in the inflammation induced rat model with respect to oxidative vulnerability. Free Radic Res 39:603–612

    Article  PubMed  CAS  Google Scholar 

  43. Bisaglia M, Venezia V, Biglieri M, Russo C, Mancini F, Milanese C, Schettini G (2004) α-Glycerylphosphorylethanolamine rescues astrocytes from mitochondrial impairment and oxidative stress induced by amyloid β-peptides. Neurochem Int 44:161–170

    Article  PubMed  CAS  Google Scholar 

  44. Conte A, Pellegrini S, Tagliazucchi D (2003) Synergistic protection of PC12 cells from beta-amyloid toxicity by resveratrol and catechin. Brain Res Bull 62:29–38

    Article  PubMed  CAS  Google Scholar 

  45. Antolin I, Mayo JC, Sainz RM, del Brio Mde L, Herrera F, Martin V, Rodriguez C (2002) Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res 943:163–173

    Article  PubMed  CAS  Google Scholar 

  46. Leon J, Acuna-Castroviejo D, Sainz RM, Mayo JC, Tan DX, Reiter RJ (2004) Melatonin and mitochondrial function. Life Sci 75:765–790

    Article  PubMed  CAS  Google Scholar 

  47. Masella R, Di Benedetto R, Vari R, Filesi C, Giovannini C (2005) Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutr Biochem 16:577–86

    Article  PubMed  CAS  Google Scholar 

  48. Han D, Handelman G, Marcocci L, Sen CK, Roy S, Kobuchi H, Tritschler HJ, Flohe L, Packer L (1997) Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors 6:321–338

    PubMed  CAS  Google Scholar 

  49. Schuurmans Stekhoven F, Bonting SL (1981) Transport adenosine triphosphatases, properties and functions. Physiol Rev 61:1–76

    Google Scholar 

  50. Thomas B, Mohanakumar KP (2004) Melatonin protects against oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the mouse nigrostriatum. J Pineal Res 36:25–32

    Article  PubMed  CAS  Google Scholar 

  51. Liu L, Li Y, Van Eldik LJ, Griffin WS, Barger SW (2005) S100B-induced microglial and neuronal IL-1 expression is mediated by cell type-specific transcription factors. J Neurochem 92:546–553

    Article  PubMed  CAS  Google Scholar 

  52. Jang MH, Jung SB, Lee MH, Kim CJ, Oh YT, Kang I, Kim J, Kim EH (2005) Melatonin attenuates amyloid beta25–35-induced apoptosis in mouse microglial BV2 cells Neurosci Lett 380:26–31

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Padmashri Dr. T. Ramasami, Director, Central Leather Research Institute, Chennai, for his kind permission to publish this work. The authors E.P.J and Dr. J.G.M thank the Council of Scientific and Industrial Research (CSIR, New Delhi), for awarding fellowships. We thank Dr. S. Kathiroli, Director, National Institute of Ocean Technology, Chennai, for extending the HPLC-EC facility required for this work. Finally, we thank the reviewers for their valuable comments and suggestion.

Author information

Authors and Affiliations

  1. Bio-Organic and Neurochemistry Laboratory, Central Leather Research Institute, Adyar, Chennai, 600 020, Tamilnadu, India

    E. Philip Jesudason, J. Gunasingh Masilamoni & R. Jayakumar

  2. Department of Biochemistry, Sri Ramachandra Medical College and Research Institute (Deemed University), Chennai, 600 116, India

    B’Joe Baben & Ben S. Ashok

  3. National Institute of Ocean Technology, Chennai, 601 302, India

    R. Kirubagaran

  4. Department of Biotechnology, Sri Ramachandra Medical College and Research Institute (Deemed University), Chennai, 600 116, India

    W. Charles E. Jebaraj

Authors
  1. E. Philip Jesudason
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B’Joe Baben
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ben S. Ashok
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Gunasingh Masilamoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Kirubagaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W. Charles E. Jebaraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Jayakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R. Jayakumar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jesudason, E.P., Baben, B., Ashok, B.S. et al. Anti-inflammatory effect of melatonin on Aβ vaccination in mice. Mol Cell Biochem 298, 69–81 (2007). https://doi.org/10.1007/s11010-006-9353-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-006-9353-x

Keywords

Search

Navigation