Psychopharmacology

, Volume 220, Issue 1, pp 183–193 | Cite as

Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity

  • Joanna E. Fardell
  • Janette Vardy
  • Jeanette D. Shah
  • Ian N. Johnston
Original Investigation

Abstract

Rationale

Studies in women with breast cancer, and in animal models, have demonstrated that chemotherapy can have a negative impact on cognitive function. Which chemotherapy agents cause problems with cognition and the aetiology of the impairment is unknown. Furthermore, there is no proven treatment.

Objectives

This study aimed to evaluate the effects of 5-fluorouracil (5FU) and oxaliplatin (OX) chemotherapy agents commonly used to treat colorectal cancer on cognition in laboratory rodents. Furthermore, we assessed physical activity as a potential remedy for the observed chemotherapy-induced cognitive deficits.

Results

In rodents, treatment with 5FU and OX alone impairs memory as measured by novel object recognition. But combined treatment appears to have greater detrimental effects on hippocampal-dependent tasks, contextual fear recall and spatial reference memory (water maze), yet had no effect on cued fear recall, a non-hippocampal task. These impairments were prevented by 4 weeks of wheel running overnight after 5FU/OX treatment. We found a significant interaction between chemotherapy and exercise: rats receiving both 5FU/OX and exercise had improved cognition relative to non-exercising 5FU/OX rats on novel object recognition and spatial reference memory.

Conclusions

The combination 5FU/OX had a significant impact on cognition. However, rats treated with 5FU/OX that exercised post chemotherapy had improved cognition relative to non-exercising rats. This suggests that physical activity may prove useful in ameliorating the cognitive impairments induced by 5FU/OX.

Keywords

Chemotherapy Cognition Oxaliplatin 5-Fluorouracil Exercise 

References

  1. Abraham J, Haut MW, Moran MT, Filburn S, Lemiuex S, Kuwabara H (2008) Adjuvant chemotherapy for breast cancer: effects on cerebral white matter seen in diffusion tensor imaging. Clin Breast Canc 8:88–91CrossRefGoogle Scholar
  2. Blokland A, Geraerts E, Been M (2004) A detailed analysis of rats’ spatial memory in a probe trial of a Morris task. Behav Brain Res 154:71–75PubMedCrossRefGoogle Scholar
  3. Bourke RS, West CR, Chheda G, Tower DB (1973) Kinetics of entry and distribution of 5-fluorouracil in cerebrospinal fluid and brain following intravenous injection in a primate. Canc Res 33:1735–1746Google Scholar
  4. Boyette-Davis JA, Fuchs PN (2009) Differential effects of paclitaxel treatment on cognitive functioning and mechanical sensitivity. Neurosci Lett 453:170–174PubMedCrossRefGoogle Scholar
  5. Cavaletti G, Tredici G, Petruccioli MG, Donde E, Tredici P, Marmiroli P, Minoia C, Ronchi A, Bayssas M, Etienne GG (2001) Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J Canc 37:2457–2463CrossRefGoogle Scholar
  6. Colcombe S, Kramer AF (2003) Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci 14:125–130PubMedCrossRefGoogle Scholar
  7. Courneya KS, Friedenreich CM, Sela RA, Quinney HA, Rhodes RE, Handman M (2003) The group psychotherapy and home-based physical exercise (group-hope) trial in cancer survivors: physical fitness and quality of life outcomes. Psycho Oncol 12:357–374CrossRefGoogle Scholar
  8. D’Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Rev 36:60–90PubMedCrossRefGoogle Scholar
  9. de Ruiter MB, Reneman L, Boogerd W, Veltman DJ, van Dam FS, Nederveen AJ, Boven E, Schagen SB (2011) Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer. Hum Brain Mapp 32(8):1206–1219PubMedCrossRefGoogle Scholar
  10. Di Cristo G, Berardi N, Cancedda L, Pizzorusso T, Putignano E, Ratto GM, Maffei L (2001) Requirement of ERK activation for visual cortical plasticity. Science 292:2337–2340PubMedCrossRefGoogle Scholar
  11. ElBeltagy M, Mustafa S, Umka J, Lyons L, Salman A, Chur-yoe GT, Bhalla N, Bennett G, Wigmore PM (2010) Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. Behav Brain Res 208:112–117PubMedCrossRefGoogle Scholar
  12. Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, White SM, Wojcicki TR, McAuley E, Kramer AF (2009) Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus 19:1030–1039PubMedCrossRefGoogle Scholar
  13. Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo CJ, Palmer TD (2003) VEGF is necessary for exercise-induced adult hippocampal neurogenesis. Eur J Neurosci 18:2803–2812PubMedCrossRefGoogle Scholar
  14. Fardell JE, Vardy J, Logge W, Johnston I (2010) Single high dose treatment with methotrexate causes long-lasting cognitive dysfunction in laboratory rodents. Pharmacol Biochem Behav 97:333–339PubMedCrossRefGoogle Scholar
  15. Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR (2004) Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague–Dawley rats in vivo. Neuroscience 124:71–79PubMedCrossRefGoogle Scholar
  16. Fendt M, Fanselow MS (1999) The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev 23:743–760PubMedCrossRefGoogle Scholar
  17. Foley JJ, Raffa RB, Walker EA (2008) Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory. Psychopharmacology 199:527–538PubMedCrossRefGoogle Scholar
  18. Formica V, Leary A, Cunningham D, Chua YJ (2006) 5-Fluorouracil can cross brain–blood barrier and cause encephalopathy: should we expect the same from capecitabine? a case report on capecitabine-induced central neurotoxicity progressing to coma. Canc Chemother Pharmacol 58:276–278CrossRefGoogle Scholar
  19. Forwood SE, Winters BD, Bussey TJ (2005) Hippocampal lesions that abolish spatial maze performance spare object recognition memory at delays of up 48 h. Hippocampus 15:347–355PubMedCrossRefGoogle Scholar
  20. Gandal MJ, Ehrlichman RS, Rudnick ND, Siegel SJ (2008) A novel electrophysiological model of chemotherapy-induced cognitive impairments in mice. Neuroscience 157:95–104PubMedCrossRefGoogle Scholar
  21. Gaskin S, Tremblay A, Mumby DG (2003) Retrograde and anterograde object recognition in rats with hippocampal lesions. Hippocampus 13:962–969PubMedCrossRefGoogle Scholar
  22. Hammond RS, Tull LE, Stackman RW (2004) On the delay-dependent involvement of the hippocampus in object recognition memory. Neurobiol Learn Mem 82:26–34PubMedCrossRefGoogle Scholar
  23. Han R, Yang YM, Dietrich J, Luebke A, Mayer-Proschel M, Noble M (2008) Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. J Biol 7:12PubMedCrossRefGoogle Scholar
  24. Hayes SC, Spence RR, Galvao DA, Newton RU (2009) Australian Association for Exercise and Sport Science position stand: optimising cancer outcomes through exercise. J Sci Med Sport 12:428–434PubMedCrossRefGoogle Scholar
  25. Hillman CH, Erickson KI, Kramer AF (2008) Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci 9:58–65PubMedCrossRefGoogle Scholar
  26. Jacobs SS, Fox E, Dennie C, Morgan LB, McCully CL, Balis FM (2005) Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates. Clin Canc Res 11:1669–1674CrossRefGoogle Scholar
  27. Jacobs S, McCully CL, Murphy RF, Bacher J, Balis FM, Fox E (2010) Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates. Canc Chemother Pharmacol 65:817–824CrossRefGoogle Scholar
  28. Joshi G, Sultana R, Tangpong J, Cole MP, St Clair DK, Vore M, Estus S, Butterfield DA (2005) Free radical mediated oxidative stress and toxic side effects in brain induced by the anti cancer drug adriamycin: insight into chemobrain. Free Radic Res 39:1147–1154PubMedCrossRefGoogle Scholar
  29. Konat GW, Kraszpulski M, James I, Zhang HT, Abraham J (2008) Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats. Metab Brain Dis 23:325–333PubMedCrossRefGoogle Scholar
  30. Kyosseva SV (2004) Mitogen-activated protein kinase signaling. Int Rev Neurobiol 59:201–220PubMedCrossRefGoogle Scholar
  31. Lee GD, Longo DL, Wang Y, Rifkind JM, Abdul-Raman L, Mamczarz JA, Duffy KB, Spangler EL, Taub DD, Mattson MP, Ingram DK (2006) Transient improvement in cognitive function and synaptic plasticity in rats following cancer chemotherapy. Clin Canc Res 12:198–205CrossRefGoogle Scholar
  32. Li CQ, Liu D, Huang L, Wang H, Zhang JY, Luo XG (2008) Cytosine arabinoside treatment impairs the remote spatial memory function and induces dendritic retraction in the anterior cingulate cortex of rats. Brain Res Bull 77:237–240PubMedCrossRefGoogle Scholar
  33. Ling B, Coudore-Civiale MA, Balayssac D, Eschalier A, Coudore F, Authier N (2007) Behavioral and immunohistological assessment of painful neuropathy induced by a single oxaliplatin injection in the rat. Toxicology 234:176–184PubMedCrossRefGoogle Scholar
  34. MacLeod JE, DeLeo JA, Hickey WF, Ahles TA, Saykin AJ, Ucci DJB (2007) Cancer chemotherapy impairs contextual but not cue-specific fear memory. Behav Brain Res 181:168–172PubMedCrossRefGoogle Scholar
  35. Mar Fan HG, Clemons M, Xu W, Chemerynsky I, Breunis H, Braganza S, Tannock IF (2008) A randomised, placebo-controlled, double-blind trial of the effects of d-methylphenidate on fatigue and cognitive dysfunction in women undergoing adjuvant chemotherapy for breast cancer. Support Care Canc 16:577–583CrossRefGoogle Scholar
  36. Marks BL, Madden DJ, Bucur B, Provenzale JM, White LE, Cabeza R, Huettel SA (2007) Role of aerobic fitness and aging on cerebral white matter integrity. Ann N Y Acad Sci 1097:171–174PubMedCrossRefGoogle Scholar
  37. Mustafa S, Walker A, Bennett G, Wigmore PM (2008) 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 28:323–330PubMedCrossRefGoogle Scholar
  38. Norcini M, Vivoli E, Galeotti N, Bianchi E, Bartolini A, Ghelardini C (2009) Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat. Pain 146:141–147PubMedCrossRefGoogle Scholar
  39. Park SB, Krishnan AV, Lin CS, Goldstein D, Friedlander M, Kiernan MC (2008) Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Curr Med Chem 15:3081–3094PubMedCrossRefGoogle Scholar
  40. Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274–285PubMedCrossRefGoogle Scholar
  41. Radak Z, Kaneko T, Tahara S, Nakamoto H, Pucsok J, Sasvari M, Nyakas C, Goto S (2001) Regular exercise improves cognitive function and decreases oxidative damage in rat brain. Neurochem Int 38:17–23PubMedCrossRefGoogle Scholar
  42. Saykin AJ, Ahles TA, McDonald BC (2003) Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives. Semin Clin Neuropsychiatry 8:201–216PubMedCrossRefGoogle Scholar
  43. Seigers R, Fardell JE (2011) Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev 35:729–741PubMedCrossRefGoogle Scholar
  44. Seigers R, Schagen SB, Beerling W, Boogerd W, Van Tellingen O, Van Dam F, Koolhaas JM, Buwalda B (2008) Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav Brain Res 186:168–175PubMedCrossRefGoogle Scholar
  45. Seigers R, Schagen SB, Coppens CM, van der Most PJ, van Dam FSAM, Koolhaas JM, Buwalda B (2009) Methotrexate decreases hippocampal cell proliferation and induces memory deficits in rats. Behav Brain Res 201:279–284PubMedCrossRefGoogle Scholar
  46. Shilling V, Jenkins V (2007) Self-reported cognitive problems in women receiving adjuvant therapy for breast cancer. Eur J Oncol Nurs 11:6–15PubMedCrossRefGoogle Scholar
  47. Sik A, van Nieuwehuyzen P, Prickaerts J, Blokland A (2003) Performance of different mouse strains in an object recognition task. Behav Brain Res 147:49–54PubMedCrossRefGoogle Scholar
  48. Soni V, Kohli DV, Jain SK (2008) Transferrin-conjugated liposomal system for improved delivery of 5-fluorouracil to brain. J Drug Target 16:73–78PubMedCrossRefGoogle Scholar
  49. Trejo JL, Llorens-Martin MV, Torres-Aleman I (2008) The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. Mol Cell Neurosci 37:402–411PubMedCrossRefGoogle Scholar
  50. van Praag H, Kempermann G, Gage FH (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2:266–270PubMedCrossRefGoogle Scholar
  51. Vardy J, Tannock I (2007) Cognitive function after chemotherapy in adults with solid tumours. Crit Rev Oncol Hematol 63:183–202PubMedCrossRefGoogle Scholar
  52. Vardy JL, Rourke S, Pond GR, Galica J, Park A, Dhillon H, Clarke SJ, Tannock IF (2010) Cognitive function and fatigue in cancer patients after chemotherapy: a longitudinal cohort study in patients with colorectal cancer (CRC). ICCTF, Cognition & Cancer Conference. ICCTF, New YorkGoogle Scholar
  53. Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:2580–2590PubMedCrossRefGoogle Scholar
  54. Verstappen CC, Heimans JJ, Hoekman K, Postma TJ (2003) Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs 63:1549–1563PubMedCrossRefGoogle Scholar
  55. Winocur G, Vardy J, Binns MA, Kerr L, Tannock I (2006) The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice. Pharmacol Biochem Behav 85:66–75PubMedCrossRefGoogle Scholar
  56. Winters BD, Bussey TJ (2005) Transient inactivation of perirhinal cortex disrupts encoding, retrieval, and consolidation of object recognition memory. J Neurosci 25:52–61PubMedCrossRefGoogle Scholar
  57. Winters BD, Saksida LM, Bussey TJ (2008) Object recognition memory: neurobiological mechanisms of encoding, consolidation and retrieval. Neurosci Biobehav Rev 32:1055–1070PubMedCrossRefGoogle Scholar
  58. Zhang GR, Wang X, Kong L, Lu XG, Lee B, Liu M, Sun M, Franklin C, Cook RG, Geller AI (2005) Genetic enhancement of visual learning by activation of protein kinase C pathways in small groups of rat cortical neurons. J Neurosci 25:8468–8481PubMedCrossRefGoogle Scholar
  59. Zhang G, Liu M, Cao H, Kong L, Wang X, O'Brien JA, Wu S, Cook RG, Geller AI (2009) Improved spatial learning in aged rats by genetic activation of protein kinase C in small groups of hippocampal neurons. Hippocampus 19:413–423PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Joanna E. Fardell
    • 1
    • 3
  • Janette Vardy
    • 2
    • 3
  • Jeanette D. Shah
    • 1
  • Ian N. Johnston
    • 1
  1. 1.School of PsychologyUniversity of SydneySydneyAustralia
  2. 2.Sydney Cancer CentreUniversity of SydneySydneyAustralia
  3. 3.Cancer Institute New South WalesSydneyAustralia

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