title: Chemotherapy-induced cognitive impairment is associated with decreases in cell proliferation and histone modifications.
abstract: BACKGROUND
  In this study, we examined the effects of cyclophosphamide, methothrexate, and 5-Fluorouracil (CMF) drug combination on various aspects of learning and memory. We also examined the effects of CMF on cell proliferation and chromatin remodeling as possible underlying mechanisms to explain chemotherapy-associated cognitive dysfunction. Twenty-four adult female Wistar rats were included in the study and had minimitter implantation for continuous activity monitoring two weeks before the chemotherapy regimen was started. Once baseline activity data were collected, rats were randomly assigned to receive either CMF or saline injections given intraperitoneally. Treatments were given once a week for a total of 4 weeks. Two weeks after the last injection, rats were tested in the water maze for spatial learning and memory ability as well as discrimination learning. Bromodeoxyuridine (BrdU) injection was given at 100 mg/Kg intraperitoneally 4 hours prior to euthanasia to determine hippocampal cell proliferation while histone acetylation and histone deacetylase activity was measured to determine CMF effects on chromatin remodeling.
  
  
  RESULTS
  Our data showed learning and memory impairment following CMF administration independent of the drug effects on physical activity. In addition, CMF-treated rats showed decreased hippocampal cell proliferation, associated with increased histone acetylation and decreased histone deacetylase activity.
  
  
  CONCLUSIONS
  These results suggest the negative consequences of chemotherapy on brain function and that anti-cancer drugs can adversely affect the self-renewal potential of neural progenitor cells and also chromatin remodeling in the hippocampus. The significance of our findings lie on the possible usefulness of animal models in addressing the clinical phenomenon of 'chemobrain.'
authors.affiliation: Department of Adult Health, Wayne State University, Detroit, MI 48202, USA. tbriones@wayne.edu
authors.forename: Teresita L
authors.initials: TL
authors.lastname: Briones
authors.forename: Julie
authors.initials: J
authors.lastname: Woods
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects* / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D006655:Histone Deacetylases