title: Fluoxetine counteracts the cognitive and cellular effects of 5-fluorouracil in the rat hippocampus by a mechanism of prevention rather than recovery.
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.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Lyons
authors.forename: Maha
authors.initials: M
authors.lastname: ElBeltagy
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bennett
authors.forename: Peter
authors.initials: P
authors.lastname: Wigmore
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects; D001835:Body Weight / Q000187:drug effects; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced / Q000517:prevention & control*; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004326:Drinking / Q000187:drug effects; D005472:Fluorouracil / Q000009:adverse effects*; D005473:Fluoxetine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects; D051381:Rats; D013028:Space Perception / Q000187:drug effects; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects
chemical_list: D018687:Antidepressive Agents, Second-Generation; D000964:Antimetabolites, Antineoplastic; D019394:Ki-67 Antigen; D005473:Fluoxetine; D001973:Bromodeoxyuridine; D005472:Fluorouracil