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The impact of sustained and intermittent docetaxel chemotherapy regimens on cognition and neural morphology in healthy mice

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Abstract

Rationale

A subset of cancer survivors demonstrates impairments in cognition long after chemotherapy completion. At present, it is unclear whether these changes are due to direct neurotoxic effects of chemotherapy.

Objectives

This study examined the impact of variable docetaxel (DTX) chemotherapy dosing on brain DTX exposure via analyses of neural morphology and changes in cognition.

Methods

Male CD-1 mice were treated with DTX either intermittently (8 mg/kg i.p. weekly) or via a sustained delivery system (DTX-PoLigel), which continuously releases DTX. Both groups received total DTX doses of 32 mg/kg. Mice were assessed on the novel object recognition (NOR) task and the Morris water maze (MWM) shortly after treatment.

Results

Post-treatment behavioral testing demonstrated impaired NOR in mice treated with either dosing schedule relative to controls. No differences were observed between groups in MWM training and initial testing, though control mice performed better than chance while DTX-treated mice did not. Appreciable amounts of DTX were found in the brain after both treatment regimens. DTX treatment did not significantly increase levels of apoptosis within the CNS. However, some elevation in neural autophagy was observed following DTX treatment. Analysis of astrocytic activation demonstrated that intermittent DTX treatment resulted in an elevation of GFAP-positive astrocytes for 48 h after administration. Sustained chemotherapy demonstrated prolonged but lower levels of astrocyte activation over 9 days following implantation.

Conclusions

DTX treatment induced cognitive impairment shortly after treatment. Further, these findings suggest an association between DTX dosing, neurotoxicity, and cognitive effects.

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Abbreviations

BBB:

Blood–brain barrier

CNS:

Central nervous system

DAPI:

4′,6-Diamidino-2-phenylindole

DTX:

Docetaxel

GFAP:

Glial fibrillary acidic protein

HPLC–MS/MS:

High-performance liquid chromatography tandem mass spectrometry

i.p.:

Intraperitoneal

MWM:

Morris water maze

NOR:

Novel object recognition

P-gp:

P-glycoprotein

PTX:

Paclitaxel

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Acknowledgments

The research presented in this paper was funded by the Ontario Division of the Canadian Cancer Society (CCS grant # 019283 held by MPM and CA). Ms. Fardell would like to acknowledge the RSA funding from the Cancer Institute NSW, Australia, and the Campbell Perry International Travel Scholarship, School of Psychology, University of Sydney.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada

    Ji Zhang, Raquel De Souza, Christine Allen, Jeffrey Henderson & Micheline Piquette-Miller

  2. School of Psychology, The University of Sydney, Sydney, Australia

    Joanna E. Fardell & Ian Johnston

  3. Concord Hospital, Sydney Medical School, The University of Sydney, Sydney, Australia

    Janette Vardy

Authors
  1. Joanna E. Fardell
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  2. Ji Zhang
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  3. Raquel De Souza
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  6. Christine Allen
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  7. Jeffrey Henderson
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  8. Micheline Piquette-Miller
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Correspondence to Micheline Piquette-Miller.

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Fardell, J.E., Zhang, J., De Souza, R. et al. The impact of sustained and intermittent docetaxel chemotherapy regimens on cognition and neural morphology in healthy mice. Psychopharmacology 231, 841–852 (2014). https://doi.org/10.1007/s00213-013-3301-8

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  • DOI: https://doi.org/10.1007/s00213-013-3301-8

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