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Cognitive impact of cytotoxic agents in mice

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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.

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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.

Author information

Authors and Affiliations

  1. Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    R. Seigers & S. B. Schagen

  2. Sylics (Synaptologics BV), Amsterdam, The Netherlands

    M. Loos

  3. Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    O. Van Tellingen

  4. Department of Neuro-Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    W. Boogerd

  5. Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands

    A. B. Smit

Authors
  1. R. Seigers
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  2. M. Loos
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  3. O. Van Tellingen
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  4. W. Boogerd
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  5. A. B. Smit
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  6. S. B. Schagen
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Corresponding author

Correspondence to S. B. Schagen.

Additional information

The authors A.B. Smit and S.B. Schagen have equal contribution.

Appendices

Appendices

Fig. 14
figure 14

Mean duration per long arrest during the light phase in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Doxorubicin 10 mg/kg increased the mean duration per long arrest during the light phase compared with control animals short-term after treatment (p < 0.05). These effects were not present long-term after treatment

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Fig. 15
figure 15

Average velocity of the 95th percentile fastest long movement segments in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Docetaxel (p < 0.05), doxorubicin (both dosages p < 0.001), and topotecan (p < 0.05) decreased the average velocity of the 95th percentile fastest long movement segments compared with control animals short-term after treatment. These effects were not present long-term after treatment

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Fig. 16
figure 16

Cut-off value to separate short and long arrests in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Both dosages of doxorubicin increased the cut-off value compared with control animals (5 mg/kg p < 0.05, 10 mg/kg p < 0.001) short-term after treatment. These effects were not present long-term after treatment

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Fig. 17
figure 17

Cut-off value to separate short and long movements in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Cyclophosphamide (p < 0.05), docetaxel (p = 0.005), doxorubicin (both dosages p < 0.001), 5-FU (p < 0.05), MTX (500 mg/kg p < 0.01), and topotecan (p < 0.05) decreased the cut-off value to separate short and long movements compared with control animals short-term after treatment. This effect was reversed long-term after treatment with topotecan (p < 0.001)

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Fig. 18
figure 18

Cumulative duration of long shelter visits during the dark phase in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Docetaxel increased the cumulative duration of long shelter visits compared with control animals (p < 0.05) short-term after treatment. These effects were not present long-term after treatment

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Fig. 19
figure 19

The fraction of shelter visits with duration longer than long shelter visit threshold in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Doxorubicin (10 mg/kg) increased the fraction of long shelter visits compared with control animals (p < 0.01) short-term after treatment. These effects were not present long-term after treatment

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Fig. 20
figure 20

Cut-off value to separate intermediate and long shelter visits in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Doxorubicin (5 mg/kg, p < 0.05) increased the cut-off value to separate intermediate and long shelter visits compared with control animals short-term after treatment. Long-term after treatment, cyclophosphamide increased the cut-off value to separate intermediate and long shelter visits compared with control animals (p < 0.05)

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Fig. 21
figure 21

Cumulative duration of activity (seconds) during the dark phase in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Docetaxel treatment decreased the cumulative duration of activity compared with control animals (p < 0.05) short-term after treatment. Long-term after treatment, cyclophosphamide treatment decreased the cumulative duration of activity compared with control animals (p < 0.05)

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Fig. 22
figure 22

Mean duration per activity bout (seconds) during the dark phase in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Both cyclophosphamide and doxorubicin (10 mg/kg) treatment increased the mean duration per activity bout compared with control animals (both p < 0.05) short-term after treatment. These effects were not present long-term after treatment

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Fig. 23
figure 23

Cumulative number of visits to OnShelter zone (frequency) during the dark phase in the automated home cage short- and long-term after treatment; error bars represent standard error of the mean. Open bar: control, grey horizontal striped bar: cyclophosphamide, black horizontal striped bar: docetaxel, grey diagonal striped bar: doxorubicin 5 mg/kg, black diagonal striped bar: doxorubicin 10 mg/kg, grey vertical striped bar: 5-FU, black vertical striped bar: MTX 250 mg/kg, grey bar: MTX 500 mg/kg, black bar: topotecan. Both dosages of doxorubicin decreased the cumulative number of visits to the OnShelter zone compared with control animals (5 mg/kg, p = 0.005; 10 mg/kg, p < 0.05) short-term after treatment. These effects were not present long-term after treatment

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Seigers, R., Loos, M., Van Tellingen, O. et al. Cognitive impact of cytotoxic agents in mice. Psychopharmacology 232, 17–37 (2015). https://doi.org/10.1007/s00213-014-3636-9

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