Journal of Neural Transmission

, Volume 117, Issue 11, pp 1295–1305 | Cite as

Treadmill training restores spatial cognitive deficits and neurochemical alterations in the hippocampus of rats submitted to an intracerebroventricular administration of streptozotocin

  • Letícia Rodrigues
  • Márcio Ferreira Dutra
  • Jocemar Ilha
  • Regina Biasibetti
  • André Quincozes-Santos
  • Marina C. Leite
  • Simone Marcuzzo
  • Matilde Achaval
  • Carlos-Alberto Gonçalves
Dementias - Original Article


The intracerebroventricular infusion of streptozotocin (icv-STZ) has been largely used in research to mimic the main characteristics of Alzheimer’s disease (AD), including cognitive decline, impairment of cholinergic transmission, oxidative stress and astrogliosis. Moderate physical exercise has a number of beneficial effects on the central nervous system, as demonstrated both in animals and in human studies. This study aimed to evaluate the effect of 5-week treadmill training, in the icv-SZT model of sporadic AD, on cognitive function, oxidative stress (particularly mediated by NO) and on the astrocyte marker proteins, glial fibrillary acidic protein (GFAP) and S100B. Results confirm the spatial cognitive deficit and oxidative stress in this model, as well as astroglial alterations, particularly a decrease in CSF S100B. Physical exercise prevented these alterations, as well as increasing the hippocampal content of glutathione and GFAP per se in the CA1 region. These findings reinforce the potential neuroprotective role of moderate physical exercise. Astroglial changes observed in this dementia model contribute to understanding AD and other diseases that are accompanied by cognitive deficit.


Alzheimer’s disease Hippocampus NO-mediated oxidative stress S100B Streptozotocin Treadmill training 


  1. Adlard PA, Perreau VM, Pop V, Cotman CW (2005) Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J Neurosci 25:4217–4221CrossRefPubMedGoogle Scholar
  2. Aksu I, Topcu A, Camsari UM, Acikgoz O (2009) Effect of acute and chronic exercise on oxidant–antioxidant equilibrium in rat hippocampus, prefrontal cortex and striatum. Neurosci Lett 452:281–285CrossRefPubMedGoogle Scholar
  3. Andreazza AC, Cassini C, Rosa AR, Leite MC, de Almeida LM, Nardin P, Cunha AB, Cereser KM, Santin A, Gottfried C, Salvador M, Kapczinski F, Goncalves CA (2007) Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res 41:523–529CrossRefPubMedGoogle Scholar
  4. Berchtold NC, Chinn G, Chou M, Kesslak JP, Cotman CW (2005) Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus. Neuroscience 133:853–861CrossRefPubMedGoogle Scholar
  5. Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Mol Biol 108:347–352PubMedGoogle Scholar
  6. Cechetti F, Fochesatto C, Scopel D, Nardin P, Goncalves CA, Netto CA, Siqueira IR (2008) Effect of a neuroprotective exercise protocol on oxidative state and BDNF levels in the rat hippocampus. Brain Res 1188:182–188CrossRefPubMedGoogle Scholar
  7. Chaves ML, Camozzato AL, Ferreira ED, Piazenski I, Kochhann R, Dall’Igna O, Mazzini GS, Souza DO, Portela LV (2010) Serum levels of S100B and NSE proteins in Alzheimer’s disease patients. J Neuroinflammation 7:6CrossRefPubMedGoogle Scholar
  8. Collins A, Hill LE, Chandramohan Y, Whitcomb D, Droste SK, Reul JM (2009) Exercise improves cognitive responses to psychological stress through enhancement of epigenetic mechanisms and gene expression in the dentate gyrus. PLoS One 4:e4330CrossRefPubMedGoogle Scholar
  9. Cotman CW, Berchtold NC (2002) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25:295–301CrossRefPubMedGoogle Scholar
  10. Cui L, Hofer T, Rani A, Leeuwenburgh C, Foster TC (2009) Comparison of lifelong and late life exercise on oxidative stress in the cerebellum. Neurobiol Aging 30:903–909CrossRefPubMedGoogle Scholar
  11. Damjanac M, Rioux Bilan A, Barrier L, Pontcharraud R, Anne C, Hugon J, Page G (2007) Fluoro-Jade B staining as useful tool to identify activated microglia and astrocytes in a mouse transgenic model of Alzheimer’s disease. Brain Res 1128:40–49CrossRefPubMedGoogle Scholar
  12. de la Monte SM, Tong M, Lester-Coll N, Plater M Jr, Wands JR (2006) Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer’s disease. J Alzheimers Dis 10:89–109PubMedGoogle Scholar
  13. de la Monte SM, Neusner A, Chu J, Lawton M (2009) Epidemilogical trends strongly suggest exposures as etiologic agents in the pathogenesis of sporadic Alzheimer’s disease, diabetes mellitus, and non-alcoholic steatohepatitis. J Alzheimers Dis 17:519–529PubMedGoogle Scholar
  14. de la Torre JC (2010) Alzheimer’s disease is incurable but preventable. J Alzheimers Dis 20:861–870PubMedGoogle Scholar
  15. Ding Y, Li J, Luan X, Ding YH, Lai Q, Rafols JA, Phillis JW, Clark JC, Diaz FG (2004) Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin. Neuroscience 124:583–591CrossRefPubMedGoogle Scholar
  16. Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, Tubaro C, Giambanco I (2009) S100B’s double life: intracellular regulator and extracellular signal. Biochim Biophys Acta 1793:1008–1022CrossRefPubMedGoogle Scholar
  17. Edwards MM, Robinson SR (2006) TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer’s disease. J Neural Transm 113:1709–1715CrossRefPubMedGoogle Scholar
  18. Eggermont L, Swaab D, Luiten P, Scherder E (2006) Exercise, cognition and Alzheimer’s disease: more is not necessarily better. Neurosci Biobehav Rev 30:562–575CrossRefPubMedGoogle Scholar
  19. Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res 25:1439–1451CrossRefPubMedGoogle Scholar
  20. Erol A (2008) An integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer’s disease. J Alzheimers Dis 13:241–253PubMedGoogle Scholar
  21. Giannakopoulos P, Kovari E, Gold G, von Gunten A, Hof PR, Bouras C (2009) Pathological substrates of cognitive decline in Alzheimer’s disease. Front Neurol Neurosci 24:20–29CrossRefPubMedGoogle Scholar
  22. Gomez-Pinilla F, So V, Kesslak JP (1998) Spatial learning and physical activity contribute to the induction of fibroblast growth factor: neural substrates for increased cognition associated with exercise. Neuroscience 85:53–61CrossRefPubMedGoogle Scholar
  23. Goncalves CA, Leite MC, Nardin P (2008) Biological and methodological features of the measurement of S100B, a putative marker of brain injury. Clin Biochem 41:755–763CrossRefPubMedGoogle Scholar
  24. 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 8:65–72CrossRefPubMedGoogle Scholar
  25. Hevel JM, Marletta MA (1994) Nitric-oxide synthase assays. Methods Enzymol 233:250–258CrossRefPubMedGoogle Scholar
  26. Holmes C, Cotterell D (2009) Role of infection in the pathogenesis of Alzheimer’s disease: implications for treatment. CNS Drugs 23:993–1002CrossRefPubMedGoogle Scholar
  27. Hoyer S (2002) The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update. J Neural Transm 109:341–360CrossRefPubMedGoogle Scholar
  28. Ilha J, Araujo RT, Malysz T, Hermel EE, Rigon P, Xavier LL, Achaval M (2008) Endurance and resistance exercise training programs elicit specific effects on sciatic nerve regeneration after experimental traumatic lesion in rats. Neurorehabil Neural Repair 22:355–366PubMedGoogle Scholar
  29. Ishrat T, Khan MB, Hoda MN, Yousuf S, Ahmad M, Ansari MA, Ahmad AS, Islam F (2006) Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats. Behav Brain Res 171:9–16CrossRefPubMedGoogle Scholar
  30. Ishrat T, Parveen K, Khan MM, Khuwaja G, Khan MB, Yousuf S, Ahmad A, Shrivastav P, Islam F (2009) Selenium prevents cognitive decline and oxidative damage in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type. Brain Res 1281:117–127CrossRefPubMedGoogle Scholar
  31. Jee YS, Ko IG, Sung YH, Lee JW, Kim YS, Kim SE, Kim BK, Seo JH, Shin MS, Lee HH, Cho HJ, Kim CJ (2008) Effects of treadmill exercise on memory and c-Fos expression in the hippocampus of the rats with intracerebroventricular injection of streptozotocin. Neurosci Lett 443:188–192CrossRefPubMedGoogle Scholar
  32. Jellinger KA (2009) Recent advances in our understanding of neurodegeneration. J Neural Transm 116:1111–1162CrossRefPubMedGoogle Scholar
  33. Kim YP, Kim H, Shin MS, Chang HK, Jang MH, Shin MC, Lee SJ, Lee HH, Yoon JH, Jeong IG, Kim CJ (2004) Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats. Neurosci Lett 355:152–154CrossRefPubMedGoogle Scholar
  34. Lannert H, Hoyer S (1998) Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 112:1199–1208CrossRefPubMedGoogle Scholar
  35. Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane P, Kukull W (2006) Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 144:73–81PubMedGoogle Scholar
  36. Laurin D, Verreault R, Lindsay J, MacPherson K, Rockwood K (2001) Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol 58:498–504CrossRefPubMedGoogle Scholar
  37. Leite MC, Galland F, Brolese G, Guerra MC, Bortolotto JW, Freitas R, Almeida LM, Gottfried C, Goncalves CA (2008) A simple, sensitive and widely applicable ELISA for S100B: methodological features of the measurement of this glial protein. J Neurosci Methods 169:93–99PubMedGoogle Scholar
  38. Li J, Ding YH, Rafols JA, Lai Q, McAllister JP 2nd, Ding Y (2005) Increased astrocyte proliferation in rats after running exercise. Neurosci Lett 386:160–164CrossRefPubMedGoogle Scholar
  39. Liberto CM, Albrecht PJ, Herx LM, Yong VW, Levison SW (2004) Pro-regenerative properties of cytokine-activated astrocytes. J Neurochem 89:1092–1100CrossRefPubMedGoogle Scholar
  40. Mallikarjuna K, Nishanth K, Hou CW, Kuo CH, Sathyavelu Reddy K (2009) Effect of exercise training on ethanol-induced oxidative damage in aged rats. Alcohol 43:59–64CrossRefPubMedGoogle Scholar
  41. Marais L, Stein DJ, Daniels WM (2009) Exercise increases BDNF levels in the striatum and decreases depressive-like behavior in chronically stressed rats. Metab Brain Dis 24:587–597CrossRefPubMedGoogle Scholar
  42. Martins IJ, Berger T, Sharman MJ, Verdile G, Fuller SJ, Martins RN (2009) Cholesterol metabolism and transport in the pathogenesis of Alzheimer’s disease. J Neurochem 111:1275–1308CrossRefPubMedGoogle Scholar
  43. Melo RM, Martinho E Jr, Michelini LC (2003) Training-induced, pressure-lowering effect in SHR: wide effects on circulatory profile of exercised and nonexercised muscles. Hypertension 42:851–857CrossRefPubMedGoogle Scholar
  44. Middleton LE, Yaffe K (2009) Promising strategies for the prevention of dementia. Arch Neurol 66:1210–1215CrossRefPubMedGoogle Scholar
  45. Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25:663–674CrossRefPubMedGoogle Scholar
  46. Netto CB, Portela LV, Ferreira CT, Kieling C, Matte U, Felix T, da Silveira TR, Souza DO, Goncalves CA, Giugliani R (2005) Ontogenetic changes in serum S100B in Down syndrome patients. Clin Biochem 38:433–435CrossRefPubMedGoogle Scholar
  47. Netto CB, Conte S, Leite MC, Pires C, Martins TL, Vidal P, Benfato MS, Giugliani R, Goncalves CA (2006) Serum S100B protein is increased in fasting rats. Arch Med Res 37:683–686CrossRefPubMedGoogle Scholar
  48. Nichol KE, Parachikova AI, Cotman CW (2007) Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse. Behav Brain Res 184:124–132CrossRefPubMedGoogle Scholar
  49. Nogueira MI, Abbas SY, Campos LG, Allemandi W, Lawson P, Takada SH, Azmitia EC (2009) S100beta protein expression: gender- and age-related daily changes. Neurochem Res 34:1355–1362CrossRefPubMedGoogle Scholar
  50. Ogonovszky H, Berkes I, Kumagai S, Kaneko T, Tahara S, Goto S, Radak Z (2005) The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain. Neurochem Int 46:635–640CrossRefPubMedGoogle Scholar
  51. Parachikova A, Nichol KE, Cotman CW (2008) Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiol Dis 30:121–129CrossRefPubMedGoogle Scholar
  52. Paxinos G (1997) The rat nervous system. Academic, San DiegoGoogle Scholar
  53. Peskind ER, Griffin WS, Akama KT, Raskind MA, Van Eldik LJ (2001) Cerebrospinal fluid S100B is elevated in the earlier stages of Alzheimer’s disease. Neurochem Int 39:409–413CrossRefPubMedGoogle Scholar
  54. Ploughman M, Granter-Button S, Chernenko G, Tucker BA, Mearow KM, Corbett D (2005) Endurance exercise regimens induce differential effects on brain-derived neurotrophic factor, synapsin-I and insulin-like growth factor I after focal ischemia. Neuroscience 136:991–1001CrossRefPubMedGoogle Scholar
  55. Pope SK, Shue VM, Beck C (2003) Will a healthy lifestyle help prevent Alzheimer’s disease? Annu Rev Public Health 24:111–132CrossRefPubMedGoogle Scholar
  56. Portela LV, Tort AB, Schaf DV, Ribeiro L, Nora DB, Walz R, Rotta LN, Silva CT, Busnello JV, Kapczinski F, Goncalves CA, Souza DO (2002) The serum S100B concentration is age dependent. Clin Chem 48:950–952PubMedGoogle Scholar
  57. Rocchi A, Orsucci D, Tognoni G, Ceravolo R, Siciliano G (2009) The role of vascular factors in late-onset sporadic Alzheimer’s disease. Genetic and molecular aspects. Curr Alzheimer Res 6:224–237CrossRefPubMedGoogle Scholar
  58. Rodrigues L, Biasibetti R, Swarowsky A, Leite MC, Quincozes-Santos A, Quilfeldt JA, Achaval M, Goncalves CA (2009) Hippocampal alterations in rats submitted to streptozotocin-induced dementia model are prevented by aminoguanidine. J Alzheimers Dis 17:193–202PubMedGoogle Scholar
  59. Rosa EF, Takahashi S, Aboulafia J, Nouailhetas VL, Oliveira MG (2007) Oxidative stress induced by intense and exhaustive exercise impairs murine cognitive function. J Neurophysiol 98:1820–1826CrossRefPubMedGoogle Scholar
  60. Salim S, Sarraj N, Taneja M, Saha K, Tejada-Simon MV, Chugh G (2010) Moderate treadmill exercise prevents oxidative stress-induced anxiety-like behavior in rats. Behav Brain Res 208:545–552CrossRefPubMedGoogle Scholar
  61. Salkovic-Petrisic M, Hoyer S (2007) Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl 72:217–233Google Scholar
  62. Salmina AB (2009) Neuron–glia interactions as therapeutic targets in neurodegeneration. J Alzheimers Dis 16:485–502PubMedGoogle Scholar
  63. Saxena G, Singh SP, Agrawal R, Nath C (2008) Effect of donepezil and tacrine on oxidative stress in intracerebral streptozotocin-induced model of dementia in mice. Eur J Pharmacol 581:283–289CrossRefPubMedGoogle Scholar
  64. Sharma M, Gupta YK (2002) Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats. Life Sci 71:2489–2498CrossRefPubMedGoogle Scholar
  65. Shen H, Tong L, Balazs R, Cotman CW (2001) Physical activity elicits sustained activation of the cyclic AMP response element-binding protein and mitogen-activated protein kinase in the rat hippocampus. Neuroscience 107:219–229CrossRefPubMedGoogle Scholar
  66. Shoham S, Bejar C, Kovalev E, Weinstock M (2003) Intracerebroventricular injection of streptozotocin causes neurotoxicity to myelin that contributes to spatial memory deficits in rats. Exp Neurol 184:1043–1052CrossRefPubMedGoogle Scholar
  67. Shoham S, Bejar C, Kovalev E, Schorer-Apelbaum D, Weinstock M (2007) Ladostigil prevents gliosis, oxidative–nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats. Neuropharmacology 52:836–843CrossRefPubMedGoogle Scholar
  68. Sloane PD, Mitchell CM, Weisman G, Zimmerman S, Foley KM, Lynn M, Calkins M, Lawton MP, Teresi J, Grant L, Lindeman D, Montgomery R (2002) The Therapeutic Environment Screening Survey for Nursing Homes (TESS-NH): an observational instrument for assessing the physical environment of institutional settings for persons with dementia. J Gerontol B Psychol Sci Soc Sci 57:S69–S78PubMedGoogle Scholar
  69. Stranahan AM, Lee K, Becker KG, Zhang Y, Maudsley S, Martin B, Cutler RG, Mattson MP (2008) Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2008.10.016
  70. Swarowsky A, Rodrigues L, Biasibetti R, Leite MC, de Oliveira LF, de Almeida LM, Gottfried C, Quillfeldt JA, Achaval M, Goncalves CA (2008) Glial alterations in the hippocampus of rats submitted to ibotenic-induced lesion of the nucleus basalis magnocellularis. Behav Brain Res 190:206–211CrossRefPubMedGoogle Scholar
  71. Teixeira AM, Trevizol F, Colpo G, Garcia SC, Charao M, Pereira RP, Fachinetto R, Rocha JB, Burger ME (2008) Influence of chronic exercise on reserpine-induced oxidative stress in rats: behavioral and antioxidant evaluations. Pharmacol Biochem Behav 88:465–472CrossRefPubMedGoogle Scholar
  72. Tramontina F, Conte S, Goncalves D, Gottfried C, Portela LV, Vinade L, Salbego C, Goncalves CA (2002) Developmental changes in S100B content in brain tissue, cerebrospinal fluid, and astrocyte cultures of rats. Cell Mol Neurobiol 22:373–378CrossRefPubMedGoogle Scholar
  73. Tramontina F, Leite MC, Cereser K, de Souza DF, Tramontina AC, Nardin P, Andreazza AC, Gottfried C, Kapczinski F, Goncalves CA (2007) Immunoassay for glial fibrillary acidic protein: antigen recognition is affected by its phosphorylation state. J Neurosci Methods 162:282–286CrossRefPubMedGoogle Scholar
  74. Van Eldik LJ, Wainwright MS (2003) The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain. Restor Neurol Neurosci 21:97–108PubMedGoogle Scholar
  75. van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270CrossRefPubMedGoogle Scholar
  76. Vicente E, Boer M, Leite M, Silva M, Tramontina F, Porciuncula L, Dalmaz C, Goncalves CA (2004) Cerebrospinal fluid S100B increases reversibly in neonates of methyl mercury-intoxicated pregnant rats. Neurotoxicology 25:771–777CrossRefPubMedGoogle Scholar
  77. Vicente E, Degerone D, Bohn L, Scornavaca F, Pimentel A, Leite MC, Swarowsky A, Rodrigues L, Nardin P, de Almeida LM, Gottfried C, Souza DO, Netto CA, Goncalves CA (2009) Astroglial and cognitive effects of chronic cerebral hypoperfusion in the rat. Brain Res 1251:204–212CrossRefPubMedGoogle Scholar
  78. Viola GG, Rodrigues L, Americo JC, Hansel G, Vargas RS, Biasibetti R, Swarowsky A, Goncalves CA, Xavier LL, Achaval M, Souza DO, Amaral OB (2009) Morphological changes in hippocampal astrocytes induced by environmental enrichment in mice. Brain Res 1274:47–54CrossRefPubMedGoogle Scholar
  79. Wolf SA, Kronenberg G, Lehmann K, Blankenship A, Overall R, Staufenbiel M, Kempermann G (2006) Cognitive and physical activity differently modulate disease progression in the amyloid precursor protein (APP)-23 model of Alzheimer’s disease. Biol Psychiatry 60:1314–1323CrossRefPubMedGoogle Scholar
  80. Zhu D, Tan KS, Zhang X, Sun AY, Sun GY, Lee JC (2005) Hydrogen peroxide alters membrane and cytoskeleton properties and increases intercellular connections in astrocytes. J Cell Sci 118:3695–3703CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Letícia Rodrigues
    • 1
  • Márcio Ferreira Dutra
    • 2
  • Jocemar Ilha
    • 1
  • Regina Biasibetti
    • 2
  • André Quincozes-Santos
    • 2
  • Marina C. Leite
    • 2
  • Simone Marcuzzo
    • 1
  • Matilde Achaval
    • 1
  • Carlos-Alberto Gonçalves
    • 1
    • 2
  1. 1.Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  2. 2.Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde (ICBS)Universidade Federal do Rio Grande do SulPorto AlegreBrazil

Personalised recommendations