Fluoxetine counteracts the cognitive and cellular effects of 5-Fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery

Lyons, Laura and ELBeltagy, Maha and Bennett, Geoffrey and Wigmore, Peter (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 (1). e30010/1-e30010/8. ISSN 1932-6203

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Abstract

5-Fluorouracil (5-FU) is a cytostatic drug associated with chemotherapy-induced cognitive impairments that many cancer

patients experience after treatment. Previous work in rodents has shown that 5-FU reduces hippocampal cell proliferation, a

possible mechanism for the observed cognitive impairment, and that both effects can be reversed by co-administration of

the antidepressant, fluoxetine. In the present study we investigate the optimum time for administration of fluoxetine to

reverse or prevent the cognitive and cellular effects of 5-FU. Male Lister-hooded rats received 5 injections of 5-FU (25 mg/

kg, i.p.) over 2 weeks. Some rats were co-administered with fluoxetine (10 mg/kg/day, in drinking water) for 3 weeks before

and during (preventative) or after (recovery) 5-FU treatment or both time periods (throughout). Spatial memory was tested

using the novel location recognition (NLR) test and proliferation and survival of hippocampal cells was quantified using

immunohistochemistry. 5-FU-treated rats showed cognitive impairment in the NLR task and a reduction in cell proliferation

and survival in the subgranular zone of the dentate gyrus, compared to saline treated controls. These impairments were still

seen for rats administered fluoxetine after 5-FU treatment, but were not present when fluoxetine was administered both

before and during 5-FU treatment. The results demonstrate that fluoxetine is able to prevent but not reverse the cognitive

and cellular effects of 5-FU. This provides information on the mechanism by which fluoxetine acts to protect against 5-FU

and indicates when it would be beneficial to administer the antidepressant to cancer patients.

Item Type: Article
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Life Sciences > School of Biomedical Sciences
Identification Number: https://doi.org/10.1371/journal.pone.0030010
Depositing User: Davies, Mrs Sarah
Date Deposited: 01 Apr 2014 10:45
Last Modified: 15 Sep 2016 09:04
URI: http://eprints.nottingham.ac.uk/id/eprint/2430

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