title: Neurobiological changes by cytotoxic agents in mice.
abstract: Cognitive deficit is a frequently reported side-effect of adjuvant chemotherapy. A large number of animal studies has been performed to examine the neurobiological mechanisms underlying this phenomenon, however, definite conclusions from these studies are restricted due to differences in experimental set-up. We systematically investigated the effects of 6 cytotoxic agents on various neurobiological parameters. C57Bl/6J mice were treated with cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. The animals were sacrificed 3 or 15 weeks after treatment and the effect on neurogenesis, blood vessel density, and neuroinflammation was analyzed using immunohistochemistry. None of the cytostatic agents tested affected neurogenesis (cell survival or cell proliferation). Blood vessel density was increased in the hippocampus and prefrontal cortex 3 weeks after treatment with docetaxel and doxorubicin compared with control animals. A decrease in the number of microglial cells was observed in the prefrontal cortex after treatment with cyclophosphamide, docetaxel, 5-FU, and topotecan compared with control mice. The observed decrease in microglia cells is indicative of inflammation that occurred after treatment. Overall, the magnitude of the effects was relatively modest. Therefore, we conducted a similar study with topotecan in Abcg2;Abcb1a/b knock out and wildtype FVB mice. Animals were sacrificed 3 weeks after treatment and no notable effect was seen in hippocampal cell differentiation (DCX), microglia activation, or blood vessel density. Perhaps the FVB strain is more resistant to the neurotoxic effects of topotecan which makes this not the correct model to study the mechanism of chemotherapy-induced cognitive impairment.
authors.affiliation: Department of Psychosocial Research and Epidemiology, the Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Seigers
authors.affiliation: Sylics (Synaptologics BV), Amsterdam, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Loos
authors.affiliation: Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: O
authors.initials: O
authors.lastname: Van Tellingen
authors.affiliation: Department of Neuro-Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Boogerd
authors.affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands.
authors.forename: A B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: Department of Psychosocial Research and Epidemiology, the Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: S.Schagen@nki.nl.
authors.forename: S B
authors.initials: SB
authors.lastname: Schagen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001808:Blood Vessels / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D003072:Cognition Disorders / Q000139:chemically induced*; D003603:Cytotoxins / Q000009:adverse effects*; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D006624:Hippocampus / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects; D009446:Neurobiology; D055495:Neurogenesis / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003603:Cytotoxins; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D007166:Immunosuppressive Agents
keywords: Blood vessels; Chemotherapy; Immunohistochemistry; Inflammation; Mouse; Neurogenesis