Molecular Neurobiology

, Volume 55, Issue 5, pp 3832–3840 | Cite as

Neuroprotective Benefits of Aerobic Exercise and Organoselenium Dietary Supplementation in Hippocampus of Old Rats

  • José L. Cechella
  • Marlon R. Leite
  • Simone Pinton
  • Gilson Zeni
  • Cristina W. Nogueira


The progressive decline of neurological functions, such as learning and memory, is an unavoidable consequence of aging. Our previous work suggested that the combination of physical exercise and a diet supplemented with diphenyl diselenide improves age-related memory decline in rats. The present study investigated the effects of physical exercise and a diet supplemented with diphenyl diselenide on the levels of proteins involved in the hippocampal neuroprotection to figure out the mechanisms related to the beneficial effects of this intervention in aged rats. Male Wistar rats (27 months old) were fed daily with standard chow supplemented with 1 ppm of diphenyl diselenide and subjected to swimming training with a workload (1% of body weight, 20 min/day) for 4 weeks. The hippocampus was dissected from the brain and used for the western blot and immunohistochemistry analyses. The results of this study demonstrate that the association of diphenyl diselenide-supplemented diet and swimming exercise increased the levels of proteins involved in neuroprotection and decreased the activation of those related to apoptosis and neuroinflammation in the hippocampus of old rats. This study suggests that physical exercise and a diet supplemented with (PhSe)2 promoted neuroprotection in the hippocampus of aged rats.


Aerobic exercise Diet Selenium Neuroprotection Apoptosis Aging 



We gratefully acknowledge UFSM, CAPES, FAPERGS (no. 2239-2551/14) and CNPq (no. 441405/2014-2) for the financial support. G.Z. and C.W.N. are recipients of CNPq fellowships.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interests.


  1. 1.
    Hedden T, Gabrieli JD (2004) Insights into the ageing mind: a view from cognitive neuroscience. Nat Rev Neurosci 5(2):87–96. doi: 10.1038/nrn1323 CrossRefPubMedGoogle Scholar
  2. 2.
    Abrous DN, Koehl M, Le Moal M (2005) Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85(2):523–569. doi: 10.1152/physrev.00055.2003 CrossRefPubMedGoogle Scholar
  3. 3.
    Lu B, Nagappan G, Lu Y (2014) BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol 220:223–250. doi: 10.1007/978-3-642-45106-5_9 CrossRefPubMedGoogle Scholar
  4. 4.
    Kim SH, Ahn KS, Jeong SJ, Kwon TR, Jung JH, Yun SM, Han I, Lee SG et al (2011) Janus activated kinase 2/signal transducer and activator of transcription 3 pathway mediates icariside II-induced apoptosis in U266 multiple myeloma cells. Eur J Pharmacol 654(1):10–16. doi: 10.1016/j.ejphar.2010.11.032 CrossRefPubMedGoogle Scholar
  5. 5.
    Pollack M, Phaneuf S, Dirks A, Leeuwenburgh C (2002) The role of apoptosis in the normal aging brain, skeletal muscle, and heart. Ann N Y Acad Sci 959:93–107CrossRefPubMedGoogle Scholar
  6. 6.
    Zhao J, Wang L, Dong X, Hu X, Zhou L, Liu Q, Song B, Wu Q et al (2016) The c-Jun N-terminal kinase (JNK) pathway is activated in human interstitial cystitis (IC) and rat protamine sulfate induced cystitis. Scientific reports 6:19670. doi: 10.1038/srep19670 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Barrientos RM, Kitt MM, Watkins LR, Maier SF (2015) Neuroinflammation in the normal aging hippocampus. Neuroscience 309:84–99. doi: 10.1016/j.neuroscience.2015.03.007 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ojo JO, Rezaie P, Gabbott PL, Stewart MG (2015) Impact of age-related neuroglial cell responses on hippocampal deterioration. Front Aging Neurosci 7:57. doi: 10.3389/fnagi.2015.00057 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Al Refaie FN, Hershko C, Hoffbrand AV, Kosaryan M, Olivieri NF, Tondury P, Wonke B (1995) Results of long-term deferiprone (L1) therapy: a report by the international study group on oral iron chelators. Br J Haematol 91(1):224–229CrossRefPubMedGoogle Scholar
  10. 10.
    Cechella JL, Leite MR, Rosario AR, Sampaio TB, Zeni G (2014) Diphenyl diselenide-supplemented diet and swimming exercise enhance novel object recognition memory in old rats. Age (Dordr) 36(4):9666. doi: 10.1007/s11357-014-9666-8 CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Kim SE, Ko IG, Kim BK, Shin MS, Cho S, Kim CJ, Kim SH, Baek SS et al (2010) Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus. Exp Gerontol 45(5):357–365. doi: 10.1016/j.exger.2010.02.005 CrossRefPubMedGoogle Scholar
  12. 12.
    Kobilo T, Liu QR, Gandhi K, Mughal M, Shaham Y, van Praag H (2011) Running is the neurogenic and neurotrophic stimulus in environmental enrichment. Learn Mem 18(9):605–609. doi: 10.1101/lm.2283011 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hatfield DL, Gladyshev VN (2002) How selenium has altered our understanding of the genetic code. Mol Cell Biol 22(11):3565–3576CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mocchegiani E, Costarelli L, Giacconi R, Malavolta M, Basso A, Piacenza F, Ostan R, Cevenini E et al (2014) Micronutrient-gene interactions related to inflammatory/immune response and antioxidant activity in ageing and inflammation. A systematic review Mechanisms of ageing and development 136-137:29–49. doi: 10.1016/j.mad.2013.12.007 CrossRefPubMedGoogle Scholar
  15. 15.
    Mancini G, Raniel Straliotto M, da Rocha JB, de Bem AF (2014) Diphenyl diselenide improves the antioxidant response via activation of the Nrf-2 pathway in macrophage cells. Free Radic Biol Med 75(Suppl 1):S40. doi: 10.1016/j.freeradbiomed.2014.10.788 CrossRefPubMedGoogle Scholar
  16. 16.
    Leite MR, Marcondes Sari MH, de Freitas ML, Oliveira LP, Dalmolin L, Brandao R, Zeni G (2014) Caffeine and diphenyl diselenide improve long-term memory impaired in middle-aged rats. Exp Gerontol 53:67–73. doi: 10.1016/j.exger.2014.03.008 CrossRefPubMedGoogle Scholar
  17. 17.
    Rosa RM, Flores DG, Appelt HR, Braga AL, Henriques JA, Roesler R (2003) Facilitation of long-term object recognition memory by pretraining administration of diphenyl diselenide in mice. Neurosci Lett 341(3):217–220CrossRefPubMedGoogle Scholar
  18. 18.
    Leite MR, Cechella JL, Mantovani AC, Duarte MM, Nogueira CW, Zeni G (2015) Swimming exercise and diphenyl diselenide-supplemented diet affect the serum levels of pro- and anti-inflammatory cytokines differently depending on the age of rats. Cytokine 71(1):119–123. doi: 10.1016/j.cyto.2014.09.006 CrossRefPubMedGoogle Scholar
  19. 19.
    Paulmier C (1986) Selenoorganic functional groups. In: Paulmier C (ed) Selenium reagents and intermediates in organic synthesis, 1st edn. Pergamon Press, Oxford, pp. 25–51Google Scholar
  20. 20.
    de Bem AF, Portella Rde L, Colpo E, Duarte MM, Frediane A, Taube PS, Nogueira CW, Farina M et al (2009) Diphenyl diselenide decreases serum levels of total cholesterol and tissue oxidative stress in cholesterol-fed rabbits. Basic Clin Pharmacol Toxicol 105(1):17–23. doi: 10.1111/j.1742-7843.2009.00414.x CrossRefPubMedGoogle Scholar
  21. 21.
    Ravi Kiran T, Subramanyam MVV, Asha Devi S (2004) Swim exercise training and adaptations in the antioxidant defense system of myocardium of old rats: relationship to swim intensity and duration. Comp Biochem Physiol 137:187–196CrossRefGoogle Scholar
  22. 22.
    Chen F, Beezhold K, Castranova V (2009) JNK1, a potential therapeutic target for hepatocellular carcinoma. Biochim Biophys Acta 1796(2):242–251. doi: 10.1016/j.bbcan.2009.06.005 PubMedGoogle Scholar
  23. 23.
    Gilgun-Sherki Y, Rosenbaum Z, Melamed E, Offen D (2002) Antioxidant therapy in acute central nervous system injury: current state. Pharmacol Rev 54(2):271–284. doi: 10.1124/Pr.54.2.271 CrossRefPubMedGoogle Scholar
  24. 24.
    Farooqui T, Farooqui AA (2009) Aging: an important factor for the pathogenesis of neurodegenerative diseases. Mech Ageing Dev 130(4):203–215. doi: 10.1016/j.mad.2008.11.006 CrossRefPubMedGoogle Scholar
  25. 25.
    Glorioso C, Sibille E (2011) Between destiny and disease: genetics and molecular pathways of human central nervous system aging. Prog Neurobiol 93(2):165–181. doi: 10.1016/j.pneurobio.2010.11.006 CrossRefPubMedGoogle Scholar
  26. 26.
    Baierle M, Nascimento SN, Moro AM, Brucker N, Freitas F, Gauer B, Durgante J, Bordignon S et al (2015) Relationship between inflammation and oxidative stress and cognitive decline in the institutionalized elderly. Oxidative Med Cell Longev 2015:804198. doi: 10.1155/2015/804198 CrossRefGoogle Scholar
  27. 27.
    Jiang T, Cadenas E (2014) Astrocytic metabolic and inflammatory changes as a function of age. Aging Cell 13(6):1059–1067. doi: 10.1111/acel.12268 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    von Bernhardi R, Eugenin-von Bernhardi L, Eugenin J (2015) Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci 7:124. doi: 10.3389/fnagi.2015.00124 Google Scholar
  29. 29.
    Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304(1):1–7. doi: 10.1124/jpet.102.035048 CrossRefPubMedGoogle Scholar
  30. 30.
    Wojtera M, Sikorska B, Sobow T, Liberski PP (2005) Microglial cells in neurodegenerative disorders. Folia neuropathologica/Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 43(4):311–321Google Scholar
  31. 31.
    Ben Haim L, Carrillo-de Sauvage MA, Ceyzeriat K, Escartin C (2015) Elusive roles for reactive astrocytes in neurodegenerative diseases. Front Cell Neurosci 9:278. doi: 10.3389/fncel.2015.00278 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81(2):229–248. doi: 10.1016/j.neuron.2013.12.034 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298(5600):1911–1912. doi: 10.1126/science.1072682 CrossRefPubMedGoogle Scholar
  34. 34.
    Huang W, Lv B, Zeng H, Shi D, Liu Y, Chen F, Li F, Liu X et al (2015) Paracrine factors secreted by MSCs promote astrocyte survival associated with GFAP downregulation after ischemic stroke via p38 MAPK and JNK. J Cell Physiol 230(10):2461–2475. doi: 10.1002/jcp.24981 CrossRefPubMedGoogle Scholar
  35. 35.
    Higami Y, Shimokawa I (2000) Apoptosis in the aging process. Cell Tissue Res 301(1):125–132CrossRefPubMedGoogle Scholar
  36. 36.
    Muradian K, Schachtschabel DO (2001) The role of apoptosis in aging and age-related disease: update. Zeitschrift fur Gerontologie und Geriatrie 34(6):441–446CrossRefPubMedGoogle Scholar
  37. 37.
    Roose JP, Diehn M, Tomlinson MG, Lin J, Alizadeh AA, Botstein D, Brown PO, Weiss A (2003) T cell receptor-independent basal signaling via Erk and Abl kinases suppresses RAG gene expression. PLoS Biol 1(2):E53. doi: 10.1371/journal.pbio.0000053 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Friedman WJ (2000) Neurotrophins induce death of hippocampal neurons via the p75 receptor. J Neurosci 20(17):6340–6346PubMedGoogle Scholar
  39. 39.
    von Bohlen und Halbach O (2010) Involvement of BDNF in age-dependent alterations in the hippocampus. Frontiers in aging neuroscience 2 doi: 10.3389/fnagi.2010.00036
  40. 40.
    Barnes P, Thomas KL (2008) Proteolysis of proBDNF is a key regulator in the formation of memory. PLoS One 3(9):e3248. doi: 10.1371/journal.pone.0003248 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Greenberg ME, Xu B, Lu B, Hempstead BL (2009) New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 29(41):12764–12767. doi: 10.1523/JNEUROSCI.3566-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35(4):605–623CrossRefPubMedGoogle Scholar
  43. 43.
    Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861. doi: 10.1146/annurev.biochem.68.1.821 CrossRefPubMedGoogle Scholar
  44. 44.
    Nogueira CW, Rocha JB (2011) Toxicology and pharmacology of selenium: emphasis on synthetic organoselenium compounds. Arch Toxicol 85(11):1313–1359. doi: 10.1007/s00204-011-0720-3 CrossRefPubMedGoogle Scholar
  45. 45.
    de Bem AF, Fiuza B, Calcerrada P, Brito PM, Peluffo G, Dinis TC, Trujillo M, Rocha JB et al (2013) Protective effect of diphenyl diselenide against peroxynitrite-mediated endothelial cell death: a comparison with ebselen. Nitric oxide: biology and chemistry 31:20–30. doi: 10.1016/j.niox.2013.03.003 CrossRefGoogle Scholar
  46. 46.
    Pinto JT, Lee JI, Sinha R, MacEwan ME, Cooper AJ (2011) Chemopreventive mechanisms of alpha-keto acid metabolites of naturally occurring organoselenium compounds. Amino Acids 41(1):29–41. doi: 10.1007/s00726-010-0578-3 CrossRefPubMedGoogle Scholar
  47. 47.
    Leite MR, Cechella JL, Pinton S, Nogueira CW, Zeni G (2016) A diphenyl diselenide-supplemented diet and swimming exercise promote neuroprotection, reduced cell apoptosis and glial cell activation in the hypothalamus of old rats. Exp Gerontol 82:1–7. doi: 10.1016/j.exger.2016.05.006 CrossRefPubMedGoogle Scholar
  48. 48.
    Heck SO, Fulco BdC, Quines CB, Oliveira CS, Leite MR, Cechella JL, Nogueira CW (2017) Combined therapy with swimming exercise and a diet supplemented with diphenyl diselenide is effective against age-related changes in the hepatic metabolism of rats. J Cell Biochem 118(6):1574–1582. doi: 10.1002/jcb.25819

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • José L. Cechella
    • 1
  • Marlon R. Leite
    • 1
  • Simone Pinton
    • 2
  • Gilson Zeni
    • 1
  • Cristina W. Nogueira
    • 1
  1. 1.Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e ExatasUniversidade Federal de Santa MariaSanta MariaBrazil
  2. 2.Universidade Federal do Pampa, Campus UruguaianaUruguaianaBrazil

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