title: Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice.
abstract: Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as weight loss and fatigue.
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France; PRES Normandie Université, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Mont-Saint-Aignan, France; North-West Cancéropole (CNO), Lille, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Dubois
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France; PRES Normandie Université, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Vadim
authors.initials: V
authors.lastname: Le Joncour
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France; PRES Normandie Université, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Tonon
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France; PRES Normandie Université, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Anouar
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France; PRES Normandie Université, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Mont-Saint-Aignan, France.
authors.forename: François
authors.initials: F
authors.lastname: Proust
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France; PRES Normandie Université, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Morin
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France; PRES Normandie Université, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Mont-Saint-Aignan, France; North-West Cancéropole (CNO), Lille, France.
authors.forename: Pierrick
authors.initials: P
authors.lastname: Gandolfo
authors.affiliation: North-West Cancéropole (CNO), Lille, France; EA4700, Laboratory of Psychology and Neurosciences of Cognition and Affectivity (PSY-NCA), University of Rouen, Mont-Saint-Aignan, France; Centre François Baclesse, Caen, France; Centre Hospitalo-Universitaire, Caen, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Joly
authors.affiliation: North-West Cancéropole (CNO), Lille, France; EA4700, Laboratory of Psychology and Neurosciences of Cognition and Affectivity (PSY-NCA), University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Hilber
authors.affiliation: Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France; PRES Normandie Université, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Mont-Saint-Aignan, France; North-West Cancéropole (CNO), Lille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Castel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000502:physiology*; D003071:Cognition / Q000187:drug effects*; D003576:Electron Transport Complex IV / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D000068338:Everolimus; D007858:Learning / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D003576:Electron Transport Complex IV; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus