Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice.
Fiche publication
Date publication
décembre 2014
Journal
PloS one
Auteurs
Membres identifiés du Cancéropôle Est :
Pr PROUST François
Tous les auteurs :
Dubois M, Le Joncour V, Tonon MC, Anouar Y, Proust F, Morin F, Gandolfo P, Joly F, Hilber P, Castel H
Lien Pubmed
Résumé
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.
Mots clés
Animals, Antineoplastic Agents, administration & dosage, Cell Proliferation, drug effects, Cells, Cultured, Central Nervous System, cytology, Cognition, drug effects, Electron Transport Complex IV, metabolism, Endothelial Cells, cytology, Everolimus, Learning, drug effects, Male, Mice, Mice, Inbred C57BL, Neural Stem Cells, cytology, Ribosomal Protein S6 Kinases, 70-kDa, metabolism, Sirolimus, administration & dosage
Référence
PLoS One. 2014 12 1;9(12):e113533