title: Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy.
abstract: BACKGROUND
  Adjuvant cancer chemotherapy can cause long-lasting, cognitive deficits. It is postulated that these impairments are due to these drugs targeting neural precursors within the adult hippocampus, the loss of which has been associated with memory impairment.
  
  
  OBJECTIVE
  The present study investigates the effects of the chemotherapy, methotrexate (MTX) on spatial working memory and the proliferation and survival of the neural precursors involved in hippocampal neurogenesis, and the possible neuroprotective properties of the antidepressant fluoxetine.
  
  
  METHODS
  Male Lister hooded rats were administered MTX (75 mg/kg, two i.v. doses a week apart) followed by leucovorin rescue (i.p. 18 h after MTX at 6 mg/kg and at 26, 42 and 50 h at 3 mg/kg) and/or fluoxetine (10 mg/kg/day in drinking water for 40 days). Memory was tested using the novel location recognition (NLR) test. Using markers, cell proliferation (Ki67) and survival (bromodeoxyuridine/BrdU), in the dentate gyrus were quantified.
  
  
  RESULTS
  MTX-treated rats showed a cognitive deficit in the NLR task compared with the vehicle and fluoxetine-treated groups. Cognitive ability was restored in the group receiving both MTX and fluoxetine. MTX reduced both the number of proliferating cells in the SGZ and their survival. This was prevented by the co-administration of fluoxetine, which alone increased cell numbers.
  
  
  CONCLUSIONS
  These results demonstrate that MTX induces an impairment in spatial working memory and has a negative long-term effect on hippocampal neurogenesis, which is counteracted by the co-administration of fluoxetine. If translatable to patients, this finding has the potential to prevent the chemotherapy-induced cognitive deficits experienced by many cancer survivors.
authors.affiliation: School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK. mbxll@nottingham.ac.uk
authors.forename: Laura
authors.initials: L
authors.lastname: Lyons
authors.forename: Maha
authors.initials: M
authors.lastname: ElBeltagy
authors.forename: Jariya
authors.initials: J
authors.lastname: Umka
authors.forename: Rachel
authors.initials: R
authors.lastname: Markwick
authors.forename: Carla
authors.initials: C
authors.lastname: Startin
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Bennett
authors.forename: Peter
authors.initials: P
authors.lastname: Wigmore
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007275:Injections, Intravenous; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D008570:Memory, Short-Term / Q000187:drug effects; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000964:Antimetabolites, Antineoplastic; D018696:Neuroprotective Agents; D005473:Fluoxetine; D008727:Methotrexate