Cognitive impact of cytotoxic agents in mice
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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.
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).
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.
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.
KeywordsMice Chemotherapy Cytotoxic agent Behavior Cognition
The authors declare that the experiments performed in this manuscript are in compliance with the current laws of The Netherlands.
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.
- 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
- 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
- DeVita VT, Hellman S, Rosenberg SA (2005) Cancer: principles & practice of oncology, 7th edn. Williams & Wilkins, Lippincott, pp 332–422Google Scholar
- 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
- 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
- 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
- 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
- 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
- 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