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

Lyons, Laura; ELBeltagy, Maha; Bennett, Geoffrey; Wigmore, Peter

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.

Citation

Lyons, L., ELBeltagy, M., Bennett, G., & Wigmore, P. (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), Article e30010. https://doi.org/10.1371/journal.pone.0030010

• Journal Article Type: Article
• Publication Date: Jan 17, 2012
• Deposit Date: Apr 1, 2014
• Publicly Available Date: Apr 1, 2014
• Journal: PLoS ONE
• Electronic ISSN: 1932-6203
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 1
• Article Number: e30010
• DOI: https://doi.org/10.1371/journal.pone.0030010
• Public URL: https://nottingham-repository.worktribe.com/output/709073
• Publisher URL: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0030010