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Psychopharmacology

, Volume 232, Issue 1, pp 17–37 | Cite as

Cognitive impact of cytotoxic agents in mice

  • R. Seigers
  • M. Loos
  • O. Van Tellingen
  • W. Boogerd
  • A. B. Smit
  • S. B. SchagenEmail author
Original Investigation

Abstract

Rationale and objectives

Adjuvant chemotherapy is associated with changes in cognition in a subgroup of cancer patients. Chemotherapy is generally given as a combination of cytotoxic agents, which makes it hard to define the agent responsible for these observed changes. Literature on animal experiments has been difficult to interpret due to variance in experimental setup.

Methods

We examined the effects of cytotoxic agents administered separately on various cognitive measures in a standardized animal model. Male C57Bl/6 mice received cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. These agents represent different compound classes based on their working mechanism and are frequently prescribed in the clinic. A control group received saline. Behavioral testing started 2 or 15 weeks after treatment and included testing general measures of behavior and cognitive task performance: spontaneous behavior in an automated home cage, open field, novel location recognition (NLR), novel object recognition (NOR), Barnes maze, contextual fear conditioning, and a simple choice reaction time task (SCRTT).

Results

Cyclophosphamide, docetaxel, and doxorubicin administration affected spontaneous activity in the automated home cage. All cytotoxic agents affected memory (NLR and/or NOR). Spatial memory measured in the Barnes maze was affected after administration with doxorubicin, 5-fluorouracil, and topotecan. Decreased inhibition in the SCRTT was observed after treatment with cyclophosphamide, docetaxel, and topotecan.

Conclusions

Our data show that, in mice, a single treatment with a cytotoxic agent causes cognitive impairment. Not all cytotoxic agents affected the same cognitive domains, which might be explained by differences in working mechanisms of the various agents.

Keywords

Mice Chemotherapy Cytotoxic agent Behavior Cognition 

Notes

Acknowledgments

The authors declare that the experiments performed in this manuscript are in compliance with the current laws of The Netherlands.

Funding

This research was funded by the Dutch Cancer Society, grant number NKI 2010-4829.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

References

  1. Ahles TA, Saykin AJ (2007) Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 7:192–201PubMedCentralPubMedCrossRefGoogle Scholar
  2. Ahles TA, Root JC, Ryan EL (2012) Cancer- and cancer treatment-associated cognitive change: an update on the state of the science. J Clin Oncol 30:3675–3686PubMedCentralPubMedCrossRefGoogle Scholar
  3. Akkerman S, Prickaerts J, Steinbusch HW, Blokland A (2012) Object recognition testing: statistical considerations. Behav Brain Res 232:317–322PubMedCrossRefGoogle Scholar
  4. Barreto G, Huang TT, Giffard RG (2010) Age-related defects in sensorimotor activity, spatial learning, and memory in C57BL/6 mice. J Neurosurg Anesthesiol 22:214–219PubMedCentralPubMedCrossRefGoogle Scholar
  5. Bernard Y, Ribeiro N, Thuaud F, Turkeri G, Dirr R, Boulberdaa M, Nebigil CG, Desaubry L (2011) Flavaglines alleviate doxorubicin cardiotoxicity: implication of Hsp27. PLoS One 6:e25302PubMedCentralPubMedCrossRefGoogle Scholar
  6. Bimonte-Nelson HA, Singleton RS, Hunter CL, Price KL, Moore AB, Granholm AC (2003) Ovarian hormones and cognition in the aged female rat: I. Long-term, but not short-term, ovariectomy enhances spatial performance. Behav Neurosci 117:1395–1406PubMedCrossRefGoogle Scholar
  7. Boogerd W (1995) Neurological complications of chemotherapy. In: de Wolff FA (ed) Handbook of clinical neurology, vol 21. Intoxications of the nervous system, part II. Elsevier Science, Amsterdam, pp 527–546Google Scholar
  8. Borcel E, Perez-Alvarez L, Herrero AI, Brionne T, Varea E, Berezin V, Bock E, Sandi C, Venero C (2008) Chronic stress in adulthood followed by intermittent stress impairs spatial memory and the survival of newborn hippocampal cells in aging animals: prevention by FGL, a peptide mimetic of neural cell adhesion molecule. Behav Pharmacol 19:41–49PubMedCrossRefGoogle Scholar
  9. Briones TL, Woods J (2011) Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications. BMC Neurosci 12:124PubMedCentralPubMedCrossRefGoogle Scholar
  10. Brooks SP, Pask T, Jones L, Dunnett SB (2005) Behavioural profiles of inbred mouse strains used as transgenic backgrounds. II: cognitive tests. Genes Brain Behav 4:307–317PubMedCrossRefGoogle Scholar
  11. Christie LA, Acharya MM, Parihar VK, Nguyen A, Martirosian V, Limoli CL (2012) Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clin Cancer Res 18:1954–1965PubMedCrossRefGoogle Scholar
  12. Denenberg VH (1969) Open-field bheavior in the rat: what does it mean? Ann N Y Acad Sci 159:852–859PubMedCrossRefGoogle Scholar
  13. Dere E, Huston JP, Souza Silva MA (2007) The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev 31:673–704PubMedCrossRefGoogle Scholar
  14. DeVita VT, Hellman S, Rosenberg SA (2005) Cancer: principles & practice of oncology, 7th edn. Williams & Wilkins, Lippincott, pp 332–422Google Scholar
  15. Dietrich J (2010) Chemotherapy associated central nervous system damage. Adv Exp Med Biol 678:77–85PubMedCrossRefGoogle Scholar
  16. Dietrich J, Han R, Yang Y, Mayer-Proschel M, Noble M (2006) CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol 5:22PubMedCentralPubMedCrossRefGoogle Scholar
  17. 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
  18. ElBeltagy M, Mustafa S, Umka J, Lyons L, Salman A, Dormon K, Allcock C, Bennett G, Wigmore P (2012) The effect of 5-fluorouracil on the long term survival and proliferation of cells in the rat hippocampus. Brain Res Bull 88:514–518PubMedCrossRefGoogle Scholar
  19. 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
  20. Fardell JE, Vardy J, Shah JD, Johnston IN (2011) Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity. Psychopharmacology (Berlin) 220:183–193CrossRefGoogle Scholar
  21. 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 (Berlin) 199:527–538CrossRefGoogle Scholar
  22. Fremouw T, Fessler CL, Ferguson RJ, Burguete Y (2012) Preserved learning and memory in mice following chemotherapy: 5-fluorouracil and doxorubicin single agent treatment, doxorubicin-cyclophosphamide combination treatment. Behav Brain Res 226:154–162PubMedCrossRefGoogle Scholar
  23. Gandal MJ, Ehrlichman RS, Rudnick ND, Siegel SJ (2008) A novel electrophysiological model of chemotherapy-induced cognitive impairments in mice. Neuroscience 157:95–104PubMedCentralPubMedCrossRefGoogle Scholar
  24. Hampson E (1990) Estrogen-related variations in human spatial and articulatory-motor skills. Psychoneuroendocrinology 15:97–111PubMedCrossRefGoogle Scholar
  25. 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 7:12PubMedCentralPubMedCrossRefGoogle Scholar
  26. Janelsins MC, Roscoe JA, Berg MJ, Thompson BD, Gallagher MJ, Morrow GR, Heckler CE, Jean-Pierre P, Opanashuk LA, Gross RA (2010) IGF-1 partially restores chemotherapy-induced reductions in neural cell proliferation in adult C57BL/6 mice. Cancer Investig 28:544–553CrossRefGoogle Scholar
  27. Kemper EM, Verheij M, Boogerd W, Beijnen JH, van Tellingen O (2004) Improved penetration of docetaxel into the brain by co-administration of inhibitors of P-glycoprotein. Eur J Cancer 40:1269–1274PubMedCrossRefGoogle Scholar
  28. Kitamura Y, Hirouchi M, Kusuhara H, Schuetz JD, Sugiyama Y (2008) Increasing systemic exposure of methotrexate by active efflux mediated by multidrug resistance-associated protein 3 (mrp3/abcc3). J Pharmacol Exp Ther 327:465–473PubMedCrossRefGoogle Scholar
  29. Koppelmans V, Breteler MM, Boogerd W, Seynaeve C, Schagen SB (2013) Late effects of adjuvant chemotherapy for adult onset non-CNS cancer; cognitive impairment, brain structure and risk of dementia. Crit Rev Oncol Hematol 88:87–101PubMedCrossRefGoogle Scholar
  30. Li Y, Vijayanathan V, Gulinello M, Cole PD (2010a) Intrathecal methotrexate induces focal cognitive deficits and increases cerebrospinal fluid homocysteine. Pharmacol Biochem Behav 95:428–433PubMedCrossRefGoogle Scholar
  31. Li Y, Vijayanathan V, Gulinello ME, Cole PD (2010b) Systemic methotrexate induces spatial memory deficits and depletes cerebrospinal fluid folate in rats. Pharmacol Biochem Behav 94:454–463PubMedCrossRefGoogle Scholar
  32. Lobo ED, Balthasar JP (2003) Pharmacokinetic-pharmacodynamic modeling of methotrexate-induced toxicity in mice. J Pharm Sci 92:1654–1664PubMedCrossRefGoogle Scholar
  33. Loos M, Staal J, Schoffelmeer AN, Smit AB, Spijker S, Pattij T (2010) Inhibitory control and response latency differences between C57BL/6J and DBA/2J mice in a Go/No-Go and 5-choice serial reaction time task and strain-specific responsivity to amphetamine. Behav Brain Res 214:216–224PubMedCrossRefGoogle Scholar
  34. Loos M, Koopmans B, Aarts E, Maroteaux G, van der Sluis S, Neuro-BSIK Mouse Consortium, Verhage M, Smit AB (2013) High throughput phenotyping of spontaneous behavior: variation within and across 11 inbred mouse strains. Genes Brain BehavGoogle Scholar
  35. Lyons L, ElBeltagy M, Bennett G, Wigmore P (2011a) The effects of cyclophosphamide on hippocampal cell proliferation and spatial working memory in rat. PLoS One 6:e21445PubMedCentralPubMedCrossRefGoogle Scholar
  36. Lyons L, ElBeltagy M, Umka J, Markwick R, Startin C, Bennett G, Wigmore P (2011b) Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy. Psychopharmacology (Berlin) 215:105–115CrossRefGoogle Scholar
  37. Lyons L, ElBeltagy M, Bennett G, Wigmore P (2012) Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery. PLoS One 7:e30010PubMedCentralPubMedCrossRefGoogle Scholar
  38. Madhyastha S, Somayaji SN, Rao MS, Nalini K, Bairy KL (2002) Hippocampal brain amines in methotrexate-induced learning and memory deficit. Can J Physiol Pharmacol 80:1076–1084PubMedCrossRefGoogle Scholar
  39. Maroteaux G, Loos M, van der Sluis S, Koopmans B, Aarts E, van Gassen K, Geurts A, Largaespada DA, Spruijt BM, Stiedl O, Smit AB, Verhage M (2012) High-throughput phenotyping of avoidance learning in mice discriminates different genotypes and identifies a novel gene. Genes Brain Behav 11:772–784PubMedCentralPubMedCrossRefGoogle Scholar
  40. Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H (2002) Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts. Learn Mem 9:49–57PubMedCentralPubMedCrossRefGoogle Scholar
  41. 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
  42. Paylor R, Zhao Y, Libbey M, Westphal H, Crawley JN (2001) Learning impairments and motor dysfunctions in adult Lhx5-deficient mice displaying hippocampal disorganization. Physiol Behav 73:781–792PubMedCrossRefGoogle Scholar
  43. Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274–285PubMedCrossRefGoogle Scholar
  44. Pukhalsky A, Shmarina G, Alioshkin V (2012) Cognitive disorders in mice: cytokine signaling pathways as therapeutic targets. OMICS 16:71–77PubMedCentralPubMedCrossRefGoogle Scholar
  45. Reiriz AB, Reolon GK, Preissler T, Rosado JO, Henriques JA, Roesler R, Schwartsmann G (2006) Cancer chemotherapy and cognitive function in rodent models: memory impairment induced by cyclophosphamide in mice. Clin Cancer Res 12:5000–5001PubMedCrossRefGoogle Scholar
  46. Riad A, Bien S, Westermann D, Becher PM, Loya K, Landmesser U, Kroemer HK, Schultheiss HP, Tschope C (2009) Pretreatment with statin attenuates the cardiotoxicity of doxorubicin in mice. Cancer Res 69:695–699PubMedCrossRefGoogle Scholar
  47. Rzeski W, Pruskil S, Macke A, Felderhoff-Mueser U, Reiher AK, Hoerster F, Jansma C, Jarosz B, Stefovska V, Bittigau P, Ikonomidou C (2004) Anticancer agents are potent neurotoxins in vitro and in vivo. Ann Neurol 56:351–360PubMedCrossRefGoogle Scholar
  48. Seigers R, Fardell JE (2011) Neurobiological basis of chemotherapy-induced cognitive impairment: a review of rodent research. Neurosci Biobehav Rev 35:729–741PubMedCrossRefGoogle Scholar
  49. Seigers R, Schagen SB, Beerling W, Boogerd W, van Tellingen O, van Dam FS, 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
  50. Seigers R, Schagen SB, Coppens CM, van der Most PJ, van Dam FS, Koolhaas JM, Buwalda B (2009) Methotrexate decreases hippocampal cell proliferation and induces memory deficits in rats. Behav Brain Res 2:279–284CrossRefGoogle Scholar
  51. Sieklucka-Dziuba M, Saczonek J, Dziuba J, Kleinrok Z (1998) Central action of some cytostatics—methotrexate (MTX) and doxorubicin (DXR). II. The influence on the seizure activity and the learning and memory processes in mice. Ann Univ Mariae Curie Sklodowska [Med] 53:81–88Google Scholar
  52. van Acker SA, Kramer K, Voest EE, Grimbergen JA, Zhang J, van der Vijgh WJ, Bast A (1996) Doxorubicin-induced cardiotoxicity monitored by ECG in freely moving mice. A new model to test potential protectors. Cancer Chemother Pharmacol 38:95–101PubMedCrossRefGoogle Scholar
  53. Walker EA, Foley JJ, Clark-Vetri R, Raffa RB (2011) Effects of repeated administration of chemotherapeutic agents tamoxifen, methotrexate, and 5-fluorouracil on the acquisition and retention of a learned response in mice. Psychopharmacology (Berlin) 217:539–548CrossRefGoogle Scholar
  54. Wefel JS, Schagen SB (2012) Chemotherapy-related cognitive dysfunction. Curr Neurol Neurosci Rep 12:267–275PubMedCrossRefGoogle 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. Winocur G, Binns MA, Tannock I (2011) Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology 61:1222–1228PubMedCrossRefGoogle Scholar
  57. Winocur G, Henkelman M, Wojtowicz JM, Zhang H, Binns MA, Tannock IF (2012) The effects of chemotherapy on cognitive function in a mouse model: a prospective study. Clin Cancer Res 18:3112–3121PubMedCrossRefGoogle Scholar
  58. Winters BD, Forwood SE, Cowell RA, Saksida LM, Bussey TJ (2004) Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: heterogeneity of function within the temporal lobe. J Neurosci 24:5901–5908PubMedCrossRefGoogle Scholar
  59. Yang M, Kim JS, Song MS, Kim SH, Kang SS, Bae CS, Kim JC, Wang H, Shin T, Moon C (2010) Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits. Neurobiol Learn Mem 93:487–494PubMedCrossRefGoogle Scholar
  60. Yang M, Kim JS, Kim J, Kim SH, Kim JC, Kim J, Wang H, Shin T, Moon C (2011) Neurotoxicity of methotrexate to hippocampal cells in vivo and in vitro. Biochem Pharmacol 82:72–80PubMedCrossRefGoogle Scholar
  61. Yang M, Kim JS, Kim J, Jang S, Kim SH, Kim JC, Shin T, Wang H, Moon C (2012) Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer. Brain Res Bull 89:50–56PubMedCrossRefGoogle Scholar
  62. Yanovski JA, Packer RJ, Levine JD, Davidson TL, Micalizzi M, D'Angio G (1989) An animal model to detect the neuropsychological toxicity of anticancer agents. Med Pediatr Oncol 17:216–221PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • R. Seigers
    • 1
  • M. Loos
    • 2
  • O. Van Tellingen
    • 3
  • W. Boogerd
    • 4
  • A. B. Smit
    • 5
  • S. B. Schagen
    • 1
    Email author
  1. 1.Department of Psychosocial Research and EpidemiologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Sylics (Synaptologics BV)AmsterdamThe Netherlands
  3. 3.Division of Molecular BiologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  4. 4.Department of Neuro-OncologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  5. 5.Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus AmsterdamVU UniversityAmsterdamThe Netherlands

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