title: Chemotherapy-induced long-term alteration of executive functions and hippocampal cell proliferation: role of glucose as adjuvant.
abstract: In patients, cancer and treatments provoke cognitive impairments referred to "chemofog". Here a validated neurobehavioral animal model, the unique way to explore causal direct links between chemotherapy used in clinical practices and brain disorders, allowed investigation of the direct long-term impact of colo-rectal cancer chemotherapy on cognition and cerebral plasticity. Young and aged mice received three injections every 7 days during 2 weeks of 5-fluorouracil either alone (5-FU, 37.5 mg/kg) or in combination with oxaliplatin (3 mg/kg) or with glucose (5%). The long-term effects (from day 24 to day 60) of chemotherapy were tested on emotional reactivity, learning and memory, behavioral flexibility and hippocampal cell plasticity. 5-FU (in saline)-treated aged and also young mice exhibited specific altered cognitive flexibility and behavioral hyper-reactivity to novelty, whereas the combination 5-FU (in saline)/oxaliplatin (in glucose) did not provoke any cognitive dysfunction. We thus observed that glucose counteracted 5-FU-induced altered executive functions and hippocampal cell proliferation in vivo, and protected neural stem cells in vitro from toxicity of 5-FU or oxaliplatin. In conclusion, these data suggest that the lasting chemotherapy-induced selective impairment of executive functions, whatever the age, and associated with a reduced number of hippocampal proliferating cells, can be counteracted by co-administration with glucose.
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, Institute of Research and Biomedical Innovation (IRIB), Normandy University PRES, University of Rouen, 76821 Mont-Saint-Aignan Cedex, France; North-West Cancéropole (CNO), 59008 Lille Cedex, France.
authors.forename: M
authors.initials: M
authors.lastname: Dubois
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, Institute of Research and Biomedical Innovation (IRIB), Normandy University PRES, University of Rouen, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: N
authors.initials: N
authors.lastname: Lapinte
authors.affiliation: EA4700, Laboratory of Psychology and Neurosciences of Cognition and Affectivity (PSY-NCA), University of Rouen, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: V
authors.initials: V
authors.lastname: Villier
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, Institute of Research and Biomedical Innovation (IRIB), Normandy University PRES, University of Rouen, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: C
authors.initials: C
authors.lastname: Lecointre
authors.affiliation: EA4700, Laboratory of Psychology and Neurosciences of Cognition and Affectivity (PSY-NCA), University of Rouen, 76821 Mont-Saint-Aignan Cedex, France; North-West Cancéropole (CNO), 59008 Lille Cedex, France.
authors.forename: V
authors.initials: V
authors.lastname: Roy
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, Institute of Research and Biomedical Innovation (IRIB), Normandy University PRES, University of Rouen, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Tonon
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, Institute of Research and Biomedical Innovation (IRIB), Normandy University PRES, University of Rouen, 76821 Mont-Saint-Aignan Cedex, France; North-West Cancéropole (CNO), 59008 Lille Cedex, France.
authors.forename: P
authors.initials: P
authors.lastname: Gandolfo
authors.affiliation: Centre François Baclesse, Caen, France; Centre Hospitalo-Universitaire, Caen, France; North-West Cancéropole (CNO), 59008 Lille Cedex, France.
authors.forename: F
authors.initials: F
authors.lastname: Joly
authors.affiliation: EA4700, Laboratory of Psychology and Neurosciences of Cognition and Affectivity (PSY-NCA), University of Rouen, 76821 Mont-Saint-Aignan Cedex, France; North-West Cancéropole (CNO), 59008 Lille Cedex, France.
authors.forename: P
authors.initials: P
authors.lastname: Hilber
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, Institute of Research and Biomedical Innovation (IRIB), Normandy University PRES, University of Rouen, 76821 Mont-Saint-Aignan Cedex, France; North-West Cancéropole (CNO), 59008 Lille Cedex, France. Electronic address: helene.castel@univ-rouen.fr.
authors.forename: H
authors.initials: H
authors.lastname: Castel
mesh_terms: D000367:Age Factors; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D056344:Executive Function / Q000187:drug effects / Q000502:physiology; D005472:Fluorouracil / Q000009:adverse effects*; D005947:Glucose / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology; D009483:Neuropsychological Tests; D018697:Nootropic Agents / Q000627:therapeutic use*; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D018697:Nootropic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005947:Glucose; D005472:Fluorouracil
keywords: Aging; Chemotherapy; Executive functions; Glucose; Hippocampal proliferating cells; Mouse