Skip to main content

Advertisement

SpringerLink
Log in

Spatial memory deficits in mice induced by chemotherapeutic agents are prevented by acetylcholinesterase inhibitors

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

These studies determined whether the acetylcholinesterase inhibitors, donepezil and galantamine, both of which are approved for the treatment of cognitive deficits in Alzheimer’s disease, can prevent or reverse spatial memory deficits in mice induced by cyclophosphamide and doxorubicin, cytotoxic agents commonly used to treat breast cancer.

Methods

Female BALB/C mice were trained in the Morris water maze to identify the location of a submerged platform, and, following baseline assessment of spatial memory, received injections of cyclophosphamide and doxorubicin once per week for 4 weeks to impair spatial memory. Saline or acetylcholinesterase inhibitors were administered daily either concurrent with the chemotherapy injections (prevention) or beginning 1 week following the final chemotherapy injections (reversal), and spatial memory was assessed weekly.

Results

Spatial memory declined during and following weekly injections of cyclophosphamide and doxorubicin, and was unaltered when the acetylcholinesterase inhibitors were administered following the manifestation of chemotherapy-induced deficits. In contrast, spatial memory of mice receiving the acetylcholinesterase inhibitors concurrent with chemotherapy did not differ from that at baseline.

Conclusions

Results indicate that chemotherapy-induced spatial memory deficits in mice can be prevented, but not reversed by the use of acetylcholinesterase inhibitors concomitant with chemotherapy, suggesting that these agents should be investigated further for the prevention of chemobrain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Wieneke MH, Dienst ER (1995) Neuropsychological assessment of cognitive functioning following chemotherapy for breast cancer. Psychooncology 4:61–66

    Article  Google Scholar 

  2. Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA (2004) The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer 100(11):2292–2299. https://doi.org/10.1002/cncr.20272

    Article  CAS  PubMed  Google Scholar 

  3. 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(30):3675–3686. https://doi.org/10.1200/JCO.2012.43.0116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tannock IF, Ahles TA, Ganz PA, Van Dam FS (2004) Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J Clin Oncol 22(11):2233–2239. https://doi.org/10.1200/JCO.2004.08.094

    Article  PubMed  Google Scholar 

  5. Kohli S, Griggs JJ, Roscoe JA, Jean-Pierre P, Bole C, Mustian KM, Hill R, Smith K, Gross H, Morrow GR (2007) Self-reported cognitive impairment in patients with cancer. J Oncol Pract 3(2):54–59. https://doi.org/10.1200/JOP.0722001

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wefel JS, Saleeba AK, Buzdar AU, Meyers CA (2010) Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer 116(14):3348–3356. https://doi.org/10.1002/cncr.25098

    Article  PubMed  Google Scholar 

  7. Raffa RB (2010) Is a picture worth a thousand (forgotten) words?: neuroimaging evidence for the cognitive deficits in ‘chemo-fog’/’chemo-brain’. J Clin Pharm Ther 35(1):1–9. https://doi.org/10.1111/j.1365-2710.2009.01044.x

    Article  CAS  PubMed  Google Scholar 

  8. Koppelmans V, Breteler MM, Boogerd W, Seynaeve C, Gundy C, Schagen SB (2012) Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol 30(10):1080–1086. https://doi.org/10.1200/JCO.2011.37.0189

    Article  PubMed  Google Scholar 

  9. Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J (2004) Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging 21(7):453–478

    Article  CAS  PubMed  Google Scholar 

  10. Ribeiz SR, Bassitt DP, Arrais JA, Avila R, Steffens DC, Bottino CM (2010) Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature. CNS Drugs 24(4):303–317. https://doi.org/10.2165/11530260-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  11. Everitt BJ, Robbins TW (1997) Central cholinergic systems and cognition. Annu Rev Psychol 48:649–684. https://doi.org/10.1146/annurev.psych.48.1.649

    Article  CAS  PubMed  Google Scholar 

  12. Lawrence JA, Griffin L, Balcueva EP, Groteluschen DL, Samuel TA, Lesser GJ, Naughton MJ, Case LD, Shaw EG, Rapp SR (2016) A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy. J Cancer Surviv 10(1):176–184. https://doi.org/10.1007/s11764-015-0463-x

    Article  CAS  PubMed  Google Scholar 

  13. Winocur G, Binns MA, Tannock I (2011) Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology 61(8):1222–1228. https://doi.org/10.1016/j.neuropharm.2011.07.013

    Article  CAS  PubMed  Google Scholar 

  14. Macleod JE, DeLeo JA, Hickey WF, Ahles TA, Saykin AJ, Bucci DJ (2007) Cancer chemotherapy impairs contextual but not cue-specific fear memory. Behav Brain Res 181(1):168–172. https://doi.org/10.1016/j.bbr.2007.04.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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(3):325–333. https://doi.org/10.1007/s11011-008-9100-y

    Article  CAS  PubMed  Google Scholar 

  16. Philpot RM, Ficken M, Wecker L (2016) Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female, but not male mice. Behav Brain Res 307:165–175. https://doi.org/10.1016/j.bbr.2016.04.017

    Article  CAS  PubMed  Google Scholar 

  17. Rendeiro C, Sheriff A, Bhattacharya TK, Gogola JV, Baxter JH, Chen H, Helferich WG, Roy EJ, Rhodes JS (2016) Long-lasting impairments in adult neurogenesis, spatial learning and memory from a standard chemotherapy regimen used to treat breast cancer. Behav Brain Res 315:10–22. https://doi.org/10.1016/j.bbr.2016.07.043

    Article  PubMed  Google Scholar 

  18. Samochocki M, Hoffle A, Fehrenbacher A, Jostock R, Ludwig J, Christner C, Radina M, Zerlin M, Ullmer C, Pereira EF, Lubbert H, Albuquerque EX, Maelicke A (2003) Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. J Pharmacol Exp Ther 305(3):1024–1036. https://doi.org/10.1124/jpet.102.045773

    Article  CAS  PubMed  Google Scholar 

  19. Thomsen MS, Hansen HH, Timmerman DB, Mikkelsen JD (2010) Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des 16(3):323–343

    Article  CAS  PubMed  Google Scholar 

  20. 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(4):487–494. https://doi.org/10.1016/j.nlm.2010.01.006

    Article  CAS  PubMed  Google Scholar 

  21. 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(7):1954–1965. https://doi.org/10.1158/1078-0432.CCR-11-2000

    Article  CAS  PubMed  Google Scholar 

  22. Kitamura Y, Hattori S, Yoneda S, Watanabe S, Kanemoto E, Sugimoto M, Kawai T, Machida A, Kanzaki H, Miyazaki I, Asanuma M, Sendo T (2015) Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation. Behav Brain Res 292:184–193. https://doi.org/10.1016/j.bbr.2015.06.007

    Article  CAS  PubMed  Google Scholar 

  23. 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(2):323–330. https://doi.org/10.1111/j.1460-9568.2008.06325.x

    Article  PubMed  Google Scholar 

  24. Lyons L, ElBeltagy M, Umka J, Markwick R, Startin C, Bennett G, Wigmore P (2011) Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy. Psychopharmacology (Berl) 215(1):105–115. https://doi.org/10.1007/s00213-010-2122-2

    Article  CAS  Google Scholar 

  25. Morris RG, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297(5868):681–683

    Article  CAS  PubMed  Google Scholar 

  26. Beiko J, Lander R, Hampson E, Boon F, Cain DP (2004) Contribution of sex differences in the acute stress response to sex differences in water maze performance in the rat. Behav Brain Res 151(1–2):239–253. https://doi.org/10.1016/j.bbr.2003.08.019

    Article  PubMed  Google Scholar 

  27. Huang Y, Zhou W, Zhang Y (2012) Bright lighting conditions during testing increase thigmotaxis and impair water maze performance in BALB/c mice. Behav Brain Res 226(1):26–31. https://doi.org/10.1016/j.bbr.2011.08.043

    Article  PubMed  Google Scholar 

  28. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. J Pharmacol Pharmacother 1(2):94–99. https://doi.org/10.4103/0976-500X.72351

    Article  PubMed  PubMed Central  Google Scholar 

  29. Jenkins V, Shilling V, Deutsch G, Bloomfield D, Morris R, Allan S, Bishop H, Hodson N, Mitra S, Sadler G, Shah E, Stein R, Whitehead S, Winstanley J (2006) A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. Br J Cancer 94(6):828–834. https://doi.org/10.1038/sj.bjc.6603029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wefel JS, Witgert ME, Meyers CA (2008) Neuropsychological sequelae of non-central nervous system cancer and cancer therapy. Neuropsychol Rev 18(2):121–131. https://doi.org/10.1007/s11065-008-9058-x

    Article  PubMed  Google Scholar 

  31. Francis DD, Zaharia MD, Shanks N, Anisman H (1995) Stress-induced disturbances in Morris water-maze performance: interstrain variability. Physiol Behav 58(1):57–65

    Article  CAS  PubMed  Google Scholar 

  32. Wahlsten D, Cooper SF, Crabbe JC (2005) Different rankings of inbred mouse strains on the Morris maze and a refined 4-arm water escape task. Behav Brain Res 165(1):36–51. https://doi.org/10.1016/j.bbr.2005.06.047

    Article  PubMed  Google Scholar 

  33. Castagne V, Moser P, Roux S, Porsolt RD (2011) Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Neurosci. https://doi.org/10.1002/0471142301.ns0810as55 (Chapter 8:Unit 8 10A)

    Article  PubMed  Google Scholar 

  34. Gergalova G, Lykhmus O, Komisarenko S, Skok M (2014) α7 nicotinic acetylcholine receptors control cytochrome c release from isolated mitochondria through kinase-mediated pathways. Int J Biochem Cell Biol 49:26–31. https://doi.org/10.1016/j.biocel.2014.01.001

    Article  CAS  PubMed  Google Scholar 

  35. Genka S, Deutsch J, Stahle PL, Shetty UH, John V, Robinson C, Rapoport SI, Greig NH (1990) Brain and plasma pharmacokinetics and anticancer activities of cyclophosphamide and phosphoramide mustard in the rat. Cancer Chemother Pharmacol 27(1):1–7

    Article  CAS  PubMed  Google Scholar 

  36. von Holst H, Knochenhauer E, Blomgren H, Collins VP, Ehn L, Lindquist M, Noren G, Peterson C (1990) Uptake of adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas. Acta Neurochir (Wien) 104(1–2):13–16

    Article  Google Scholar 

  37. Janelsins MC, Mustian KM, Palesh OG, Mohile SG, Peppone LJ, Sprod LK, Heckler CE, Roscoe JA, Katz AW, Williams JP, Morrow GR (2012) Differential expression of cytokines in breast cancer patients receiving different chemotherapies: implications for cognitive impairment research. Support Care Cancer 20(4):831–839. https://doi.org/10.1007/s00520-011-1158-0

    Article  PubMed  Google Scholar 

  38. Cheung YT, Ng T, Shwe M, Ho HK, Foo KM, Cham MT, Lee JA, Fan G, Tan YP, Yong WS, Madhukumar P, Loo SK, Ang SF, Wong M, Chay WY, Ooi WS, Dent RA, Yap YS, Ng R, Chan A (2015) Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study. Ann Oncol 26(7):1446–1451. https://doi.org/10.1093/annonc/mdv206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wilson CJ, Finch CE, Cohen HJ (2002) Cytokines and cognition–the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 50(12):2041–2056

    Article  PubMed  Google Scholar 

  40. Kelley KW, Bluthe RM, Dantzer R, Zhou JH, Shen WH, Johnson RW, Broussard SR (2003) Cytokine-induced sickness behavior. Brain Behav Immun 17(Suppl 1):S112–S118

    Article  CAS  PubMed  Google Scholar 

  41. Kawashima K, Fujii T (2008) Basic and clinical aspects of non-neuronal acetylcholine: overview of non-neuronal cholinergic systems and their biological significance. J Pharmacol Sci 106(2):167–173

    Article  CAS  PubMed  Google Scholar 

  42. Tracey KJ (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Investig 117(2):289–296. https://doi.org/10.1172/JCI30555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang DW, Zhou RB, Yao YM (2009) Role of cholinergic anti-inflammatory pathway in regulating host response and its interventional strategy for inflammatory diseases. Chin J Traumatol 12(6):355–364

    CAS  PubMed  Google Scholar 

  44. Carnevale D, De Simone R, Minghetti L (2007) Microglia-neuron interaction in inflammatory and degenerative diseases: role of cholinergic and noradrenergic systems. CNS Neurol Disord Drug Targ 6(6):388–397

    Article  CAS  Google Scholar 

  45. Tsvetkova D, Obreshkova D, Zheleva-Dimitrova D, Saso L (2013) Antioxidant activity of galantamine and some of its derivatives. Curr Med Chem 20(36):4595–4608

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank April Lindon for her technical assistance during this study and Dr. Heather Jim for her valuable suggestions and feedback.

Funding

These studies were supported in part by USF Research and Innovation Proposal Enhancement Grant and the American Cancer Society Institutional Research Grant, Moffitt Cancer Center.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, 3515 East Fletcher Avenue, Tampa, FL, 33613-4706, USA

    Rex M. Philpot, M. Ficken, B. E. Johns, M. E. Engberg & L. Wecker

Authors
  1. Rex M. Philpot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Ficken
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. E. Johns
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. E. Engberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. Wecker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rex M. Philpot.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The care and use of animals were approved in accordance with guidelines set by the University of South Florida Institutional Animal Care and Use Committee, the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines of the National Centre for the Replacement, Refinement and Reduction of Animals in Research.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Philpot, R.M., Ficken, M., Johns, B.E. et al. Spatial memory deficits in mice induced by chemotherapeutic agents are prevented by acetylcholinesterase inhibitors. Cancer Chemother Pharmacol 84, 579–589 (2019). https://doi.org/10.1007/s00280-019-03881-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-019-03881-8

Keywords

Search

Navigation