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Protective Role of Melatonin on Oxidative Stress Status and RNA Expression in Cerebral Cortex and Cerebellum of AβPP Transgenic Mice After Chronic Exposure to Aluminum

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Abstract

Aluminum (Al) has been associated with pro-oxidant effects, as well as with various serious neurodegenerative diseases such as Alzheimer’s disease (AD). On the other hand, melatonin (Mel) is a known antioxidant, which can directly act as free radical scavenger, or indirectly by inducing the expression of some genes linked to the antioxidant defense. In this study, 5-month-old AßPP female transgenic (Tg2576) (Tg) and wild-type mice were fed with Al lactate supplemented in the diet (1 mg Al/g diet). Concurrently, animals received oral Mel (10 mg/kg) until the end of the study at 11 months of age. Four treatment groups were included for both Tg and wild-type mice: control, Al only, Mel only, and Al + Mel. At the end of the treatment period, cortex and cerebellum were removed and processed to examine the following oxidative stress markers: reduced glutathione, oxidized glutathione, cytosolic Cu–Zn superoxide dismutase (SOD1), glutathione reductase (GR), glutathione peroxidase, catalase (CAT), and thiobarbituric acid reactive substances. Moreover, the gene expression of SOD1, GR, and CAT was evaluated by real-time RT-PCR. The biochemical changes observed in cortex and cerebellum suggest that Al acted as a pro-oxidant agent. Melatonin exerted an antioxidant action by increasing the mRNA levels of the enzymes SOD1, CAT, and GR evaluated in presence of Al and Mel, independently on the animal model.

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References

  1. Yokel RA, Florence RL (2006) Aluminum bioavailability from the approved food additive leavening agent acid sodium aluminum phosphate, incorporated in to a baked good, is lower than from water. Toxicology 227:86–93

    Article  CAS  PubMed  Google Scholar 

  2. Albendea CD, Gómez-Trullén EM, Fuentes-Broto L, Miana-Mena FJ, Millán-Plano S, Reyes-Gonzales MC, Martínez-Ballarín E, García JJ (2007) Melatonin reduces lipid and protein oxidative damage in synaptosomes due to aluminum. J Trace Elem Med Biol 21:261–268

    Article  CAS  PubMed  Google Scholar 

  3. Tripathi S, Mahdi AA, Nawab A, Chander R, Hasan M, Siddiqui MS, Mahdi F, Mitra K, Bajpai VK (2009) Influence of age on aluminum induced lipid peroxidation and neurolipofuscin in frontal cortex of rat brain: a behavioral, biochemical and ultrastructural study. Brain Res 9:107–116

    Article  Google Scholar 

  4. Bohrer D, Bertagnolli DC, de Oliveira SM, do Nascimento PC, de Carvalho LM, Garcia SC, Arantes LC, Barros EJ (2009) Role of medication in the level of aluminium in the blood of chronic haemodialysis patients. Nephrol Dial Transplant 24:1277–1281

    Article  CAS  PubMed  Google Scholar 

  5. Domingo JL (2006) Aluminum and other metals in Alzheimer’s disease: a review of potential therapy with chelating agents. J Alzheimers Dis 10:331–341

    PubMed  Google Scholar 

  6. Exley C, Esir MM (2006) Severe cerebral congophilic angiophaty coincident with increased brain aluminum in a resident of Camelford, Cornwall, UK. J Neurol Neurosug Psychiatry 77:877–879

    Article  CAS  Google Scholar 

  7. Walton JR (2006) Aluminum in hippocampal neurons from humans with Alzheimer’s disease. Neurotoxicology 27:385–394

    Article  CAS  PubMed  Google Scholar 

  8. Yokel RA (2006) Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration. J Alzheimers Dis 10:223–253

    PubMed  Google Scholar 

  9. Drago D, Bolognin S, Zatta P (2008) Role of metal ions in the Aß oligomerization in Alzheimer’s disease and in other neurological disorders. Curr Alzheimer Res 5:500–507

    Article  CAS  PubMed  Google Scholar 

  10. Walton JR (2008) Functional impairment in aged rats chronically exposed to human range dietary aluminum equivalents. Neurotoxicology 30:82–193

    Google Scholar 

  11. Exley C (2004) The pro-oxidant activity of aluminum. Free Radic Biol Med 36:380–387

    Article  CAS  PubMed  Google Scholar 

  12. Esparza JL, Gómez M, Nogués MR, Paternain JL, Mallol J, Domingo JL (2005) Melatonin reduces oxidative stress and increases gene expression in the cerebral cortex and cerebellum of aluminum-exposed rats. J Pineal Res 39:129–136

    CAS  PubMed  Google Scholar 

  13. Gómez M, Esparza JL, Nogués MR, Giralt M, Domingo JL (2005) Pro-oxidant activity of aluminum in the rat hippocampus: gene expression of antioxidant enzymes after melatonin administration. Free Radic Biol Med 38:104–111

    Article  PubMed  Google Scholar 

  14. Di Carlo M (2009) Beta amyloid peptide: from different aggregation forms to the activation of different biochemical pathways. Eur Biophys J. doi:10.1007/s00249-009-0439-8

    PubMed  Google Scholar 

  15. Pratico D, Uryu K, Sung S, Tang S, Trojanowski JQ, Lee VMY (2002) Aluminum modulates brain amyloidosis through oxidative stress in APP transgenic mice. FASEB J 16:1138–1140

    CAS  PubMed  Google Scholar 

  16. Maynard CJ, Cappai R, Volitakis I, Cherny RA, Masters CL, Li QX, Bush AI (2006) Gender and genetic background effects on brain metal levels in APP transgenic and normal mice: implications for Alzheimer beta-amyloid pathology. J Inorg Biochem 100:952–962

    Article  CAS  PubMed  Google Scholar 

  17. Bush AI (2008) Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimers Dis 15:223–240

    CAS  PubMed  Google Scholar 

  18. Xie PI, Yokel RA (1996) Aluminum facilitation of iron mediated lipid peroxidation is dependet on substrate, pH and aluminum and iron concentrations. Arch Biochem Biophys 327:222–226

    Article  CAS  PubMed  Google Scholar 

  19. Esparza JL, Gomez M, Romeu M, Mulero M, Sanchez DJ, Mallol J, Domingo JL (2003) Aluminum-induced pro-oxidant effects in rats: protective role of exogenous melatonin. J Pineal Res 35:32–39

    Article  CAS  PubMed  Google Scholar 

  20. Gupta VB, Anitha S, Hegde ML, Zecca L, Garruto RM, Ravid R, Shankar SK, Stein R, Shanmugavelu P, Jagannatha Rao KS (2005) Aluminum in Alzheimer’s disease: are we still at a crossroad? Cell Mol Life Sci 62:143–158

    Article  CAS  PubMed  Google Scholar 

  21. Kumar V, Bal A, Gill KD (2008) Impairment of mitochondrial energy metabolism in different regions of rat brain following chronic exposure to aluminum. Brain Res 26:94–103

    Article  Google Scholar 

  22. Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147

    Article  CAS  PubMed  Google Scholar 

  23. Kaneko N, Yasui H, Takada J, Suzuki K, Sakurai H (2004) Orally administered aluminum-maltolate complex enhances oxidative stress in the organs of mice. J Inorg Biochem 98:2022–2031

    Article  CAS  PubMed  Google Scholar 

  24. García T, Esparza JL, Nogués MR, Romeu M, Domingo JL, Gómez M (2009) Oxidative stress status and RNA expression in hippocampus of an animal model of Alzheimer’s disease after chronic exposure to aluminum. Hippocampus. doi:10.1002/hipo.20612

    Google Scholar 

  25. Reiter RJ, Tan DX, Osuna C, Gitto E (2000) Actions of melatonin in the reduction of oxidative stress. J Biomed Sci 7:444–458

    Article  CAS  PubMed  Google Scholar 

  26. Hardeland R, Pandi-Perumal SR, Cardinali DP (2005) Melatonin. Int J Biochem Cell Biol 38:313–316

    Article  PubMed  Google Scholar 

  27. Pandi-Perumal SR, Srinivasan V, Maestroni GJM, Cardinalli DP, Poeggeler B, Hardeland R (2006) Melatonin. Nature’s most versatile biological signal? FEBS J 273:2813–2838

    Article  CAS  PubMed  Google Scholar 

  28. Reiter RJ, Korkmaz A (2008) Clinical aspects of melatonin. Saudi Med J 29:1537–1547

    PubMed  Google Scholar 

  29. Liu P, Zheng Y, Smith PF, Bilkey DK (2003) Changes in NOS protein expression and activity in the rat hippocampus, entorhinal and postrhinal cortices after unilateral electrolytic perirhinal cortex lesions. Hippocampus 13:561–571

    Article  CAS  PubMed  Google Scholar 

  30. Maharaj DS, Glass BD, Daya S (2007) Melatonin: new places in therapy. Biosci Rep 27:299–320

    Article  CAS  PubMed  Google Scholar 

  31. Kotler M, Rodríguez C, Sáinz RM et al (1998) Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. J Pineal Res 24:83–89

    Article  CAS  PubMed  Google Scholar 

  32. Matsubara E, Bryant-Thomas T, Pacheco Quinto J, Henry TL, Poeggeler B, Herbert D, Cruz-Sanchez F, Chyan YJ, Smith MA, Perry G, Shoji M, Abe K, Leone A, Grundke-Ikbal I, Wilson GL, Ghiso J, Williams C, Refolo LM, Pappolla MA, Chain DG, Neria E (2003) Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem 85:1001–1008

    Article  Google Scholar 

  33. Reiter RJ, Tan DX, Pappolla MA (2004) Melatonin relieves the neural oxidative burden that contributes to dementias. Ann N Y Acad Sci 1035:179–196

    Article  CAS  PubMed  Google Scholar 

  34. Ma J, Shaw VE, Mitrofanis J (2009) Does melatonin help save dopaminergic cells in MPTP-treated mice? Parkinsonism Relat Disord 15:307–314

    Article  PubMed  Google Scholar 

  35. Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ, Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, Younkin SG, Hsiao KK (1999) Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2:271–276

    Article  CAS  PubMed  Google Scholar 

  36. Rodrigo J, Fernandez-Vizcarra P, Castro-Blanco S, Bentura ML, Nieto M, Gomez-Isla T, Martinez-Murillo R, Martinez A, Serrano J, Fernandez AP (2004) Nitric oxide in the cerebral cortex of amyloid-precursor protein (SW) Tg2576 transgenic mice. Neuroscience 128:73–89

    Article  CAS  PubMed  Google Scholar 

  37. Bizon J, Prescott S, Nicolle MM (2007) Intact spatial learning in adult Tg 2576 mice. Neurobiol Aging 28:440–446

    Article  CAS  PubMed  Google Scholar 

  38. López-Toledano MA, Shelanski ML (2007) Increased neurogenesis in young transgenic mice overexpressing human APP (Sw, Ind). J Alzheimers Dis 12:229–240

    PubMed  Google Scholar 

  39. Duyckaerts C, Poitier MC, Delatour B (2008) Alzheimer disease models and human neuropathology similarities and differences. Acta Neuropathol 115:5–38

    Article  PubMed  Google Scholar 

  40. Gómez M, Esparza JL, Cabré M, García T, Domingo JL (2008) Aluminum exposure through the diet: metal levels in AβPP transgenic mice, a model for Alzheimer’s disease. Toxicology 249:214–219

    Article  PubMed  Google Scholar 

  41. Ribes D, Colomina MT, Vicens P, Domingo JL (2008) Effects of oral aluminum exposure on behavior and neurogenesis in a transgenic mouse model of Alzheimer’s disease. Exp Neurol 214:293–300

    Article  CAS  PubMed  Google Scholar 

  42. Golub MS, Germann SL, Keen CL (2003) Developmental aluminum toxicity in mice can be modulated by low concentrations of minerals (Fe, Zn, P, Ca, Mg) in the diet. Biol Trace Elem Res 93:213–226

    Article  CAS  PubMed  Google Scholar 

  43. Nogués MR, Giralt M, Romeo M, Mulero M, Sánchez-Martos V, Rodríguez E, Acuña-Castroviejo D, Mallol J (2006) Melatonin reduces oxidative stress in erythrocytes and plasma of senescence-accelerated mice. J Pineal Res 41:142–149

    Article  PubMed  Google Scholar 

  44. Hissin PJ, Hilf R (1976) A fluorometric method for determination of oxidized and reduced glutathione in tissues. Anal Biochem 74:214–226

    Article  CAS  PubMed  Google Scholar 

  45. Wheeler C, Salzman J, Elsayed N (1990) Automated assays for superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activity. Anal Biochem 184:193–199

    Article  CAS  PubMed  Google Scholar 

  46. ABI Prism 7700 (1997) Sequence detection system. User Bulletin No. 2. Revision A. Foster City, CA: Applied Biosystems

  47. Caballero B, Vega-Naredo I, Sierra V, Huidobro-Fernández C, Soria-Valles C, De Gonzalo-Calvo D, Tolivia D, Gutierrez-Cuesta J, Pallas M, Camins A, Rodriguez-Colunga MJ, Coto-Montes A (2008) Favorable effects of a prolonged treatment with melatonin on the level of oxidative damage and neurodegeneration in senescence-accelerated mice. J Pineal Res 45:302–311

    Article  CAS  PubMed  Google Scholar 

  48. Colomina MT, Roig JL, Sanchez DJ, Domingo JL (2002) Influence of age on aluminum-induced neurobehavioral effects and morphological changes in rat brain. Neurotoxicology 23:775–781

    Article  CAS  PubMed  Google Scholar 

  49. Lack B, Daya S, Nyokong T (2001) Interaction of serotonin and melatonin with sodium, potassium, calcium, lithium and aluminum. J Pineal Res 31:102–108

    Article  CAS  PubMed  Google Scholar 

  50. Candan N, Tuzmen N (2008) Very rapid quantification of malondialdehyde (MDA) in rat brain exposed to lead, aluminum and phenolic antioxidants by high-performance liquid chromatography-fluorescence detection. Neurotoxicology 29:708–713

    Article  CAS  PubMed  Google Scholar 

  51. Abd-Elghaffar SKH, El-Sokkary GH, Sharkawy AA (2005) Aluminum-induced neurotoxicity and oxidative damage in rabbits: protective effect of melatonin. Neuro Endocrinol Lett 26:609–616

    CAS  PubMed  Google Scholar 

  52. Akbulut KG, Gonül B, Akbulut H (2008) Exogenous melatonin decreases age-induced lipid peroxidation in the brain. Brain Res 1238:31–35

    Article  CAS  PubMed  Google Scholar 

  53. Rodríguez MI, Escamesm G, López LC, López A, García JA, Ortiz F, Sánchez V, Romeu M, Acuña-Castroviejo D (2008) Improved mitochondrial function and increased life span after chronic melatonin treatment in senescent prone mice. Exp Gerontol 4:749–756

    Article  Google Scholar 

  54. Antolin I, Mayo JC, Sainz RM, del Brío MI, Herrera F, Martín V, Rodriguez C (2002) Protective effects of melatonin in an experimental model of Parkinson’s disease. Brain Res 943:163–173

    Article  CAS  PubMed  Google Scholar 

  55. Baydas G, Yasea A, Tuzcu M (2005) Comparison of impact of melatonin on chronic ethanol-induced learning and memory impairment between young and aged rats. J Pineal Res 39:346–352

    Article  CAS  PubMed  Google Scholar 

  56. Srinivasan V, Pandi-Perumal SR, Cardinali D, Poeggeler B, Hardeland R (2006) Melatonin in Alzheimer’s disease and other neurodegenative disorders. Behav Brain Funct 2:15

    Article  CAS  PubMed  Google Scholar 

  57. Wu YH, Swaab DF (2005) The human pineal gland and melatonin in aging and Alzheimer’s disease. J Pineal Res 38:145–152

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

Financial support for this study was provided by the “Fondo de Investigación Sanitaria” (FIS), Ministry of Health, Spain, through grant number PI050622.

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Authors and Affiliations

  1. Laboratory of Toxicology and Environmental Health, IISPV, School of Medicine, “Rovira i Virgili” University, Sant Llorens 21, 43201, Reus, Catalonia, Spain

    Tania García, José L. Esparza, José L. Domingo & Mercedes Gómez

  2. Pharmacology Unit, School of Medicine, “Rovira i Virgili” University, 43201, Reus, Catalonia, Spain

    Montserrat Giralt & Marta Romeu

Authors
  1. Tania García
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  2. José L. Esparza
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  3. Montserrat Giralt
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  6. Mercedes Gómez
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Correspondence to Mercedes Gómez.

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García, T., Esparza, J.L., Giralt, M. et al. Protective Role of Melatonin on Oxidative Stress Status and RNA Expression in Cerebral Cortex and Cerebellum of AβPP Transgenic Mice After Chronic Exposure to Aluminum. Biol Trace Elem Res 135, 220–232 (2010). https://doi.org/10.1007/s12011-009-8490-y

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  • DOI: https://doi.org/10.1007/s12011-009-8490-y

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