Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read Online Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Antineoplastic Agents/*administration & dosage ; Central Nervous System/*physiology ; Cognition/*drug effects ; Learning/*drug effects ; Sirolimus/*analogs & derivatives; Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; Central Nervous System/cytology ; Electron Transport Complex IV/metabolism ; Endothelial Cells/cytology ; Endothelial Cells/drug effects ; Everolimus ; Male ; Mice ; Mice, Inbred C57BL ; Neural Stem Cells/cytology ; Neural Stem Cells/drug effects ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Sirolimus/administration & dosage
    • 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.
    • References:
      Endothelium. 2000;7(2):135-47. (PMID: 10865941)
      J Neurosci. 2006 Aug 2;26(31):8048-56. (PMID: 16885218)
      Diabetes. 2010 Jun;59(6):1338-48. (PMID: 20299475)
      J Neurosci. 2007 Apr 25;27(17):4716-24. (PMID: 17460084)
      Neurosci Lett. 2011 May 20;495(3):201-4. (PMID: 21458538)
      Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1013-22. (PMID: 19690069)
      Neuroscience. 2006 Aug 11;141(1):35-45. (PMID: 16650612)
      Neuroscience. 2005;135(3):691-702. (PMID: 16125863)
      J Clin Oncol. 2008 Apr 1;26(10):1596-602. (PMID: 18332467)
      Nature. 2000 Apr 6;404(6778):661-71. (PMID: 10766253)
      Clin Cancer Res. 2008 Feb 1;14(3):892-900. (PMID: 18245553)
      Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):467-72. (PMID: 11756682)
      J Neurosci. 2009 May 27;29(21):6860-70. (PMID: 19474313)
      J Comp Neurol. 1999 Dec 13;415(2):145-59. (PMID: 10545156)
      Am J Physiol Endocrinol Metab. 2012 Dec 15;303(12):E1446-58. (PMID: 23047987)
      Science. 2006 May 12;312(5775):927-30. (PMID: 16690869)
      J Biol Chem. 1995 Jan 13;270(2):815-22. (PMID: 7822316)
      Neurobiol Learn Mem. 2008 Mar;89(3):338-51. (PMID: 18039584)
      Physiol Behav. 2005 Dec 15;86(5):773-95. (PMID: 16289609)
      Mol Neurodegener. 2010 Jun 22;5:26. (PMID: 20569486)
      Nature. 1982 Jun 24;297(5868):681-3. (PMID: 7088155)
      J Clin Oncol. 2007 Aug 10;25(23):3559. (PMID: 17687168)
      J Neurosci. 2009 May 27;29(21):6964-72. (PMID: 19474323)
      Cancer. 2010 Sep 15;116(18):4256-65. (PMID: 20549832)
      Neuropharmacology. 2014 Apr;79:234-48. (PMID: 24291465)
      Nat Rev Cancer. 2004 May;4(5):335-48. (PMID: 15122205)
      Cell Commun Adhes. 2001;8(1):1-13. (PMID: 11775025)
      Clin Cancer Res. 2006 Sep 1;12(17):5165-73. (PMID: 16951235)
      Exp Brain Res. 1998 Jul;121(1):35-45. (PMID: 9698188)
      Brain Res. 1979 Jul 27;171(1):11-28. (PMID: 223730)
      Neuroscience. 2008 Nov 11;157(1):95-104. (PMID: 18835334)
      Pharmacol Biochem Behav. 2006 Sep;85(1):66-75. (PMID: 16935324)
      Peptides. 2009 Nov;30(11):2052-9. (PMID: 19660508)
      Biochim Biophys Acta. 2010 Mar;1804(3):433-9. (PMID: 20005306)
      Trends Neurosci. 2010 Feb;33(2):67-75. (PMID: 19963289)
      J Cell Mol Med. 2009 Jul;13(7):1371-80. (PMID: 18466352)
      Pediatr Res. 2011 Aug;70(2):159-65. (PMID: 21532529)
      Peptides. 2010 Dec;31(12):2185-92. (PMID: 20804797)
      Psychooncology. 2011 Dec;20(12):1251-8. (PMID: 21254307)
      Clin Cancer Res. 2007 Jul 15;13(14):4261-70. (PMID: 17634556)
      Eur J Neurosci. 2006 Jun;23(12):3375-84. (PMID: 16820027)
      Oncologist. 2010;15(11):1135-46. (PMID: 21051659)
      Nat Neurosci. 1999 Mar;2(3):260-5. (PMID: 10195219)
      Trends Genet. 2008 Oct;24(10):498-510. (PMID: 18774199)
      N Engl J Med. 2006 Mar 2;354(9):980-2; discussion 980-2. (PMID: 16510760)
      J Clin Oncol. 2009 May 1;27(13):2278-87. (PMID: 19332717)
      Br J Cancer. 2008 Mar 11;98(5):923-30. (PMID: 18319715)
      Cardiovasc Res. 2008 Jun 1;78(3):563-71. (PMID: 18250144)
      Cancer Chemother Pharmacol. 2013 May;71(5):1219-29. (PMID: 23455451)
      Neurobiol Learn Mem. 2008 Jul;90(1):28-35. (PMID: 18316213)
      Drug Discov Today. 2007 Feb;12(3-4):112-24. (PMID: 17275731)
      J Comp Neurol. 2003 Sep 15;464(2):220-37. (PMID: 12898614)
      J Neurosci. 2000 Dec 15;20(24):9104-10. (PMID: 11124987)
      Am J Physiol Regul Integr Comp Physiol. 2008 Apr;294(4):R1276-84. (PMID: 18287224)
      Cancer Manag Res. 2010 Mar 09;2:61-70. (PMID: 21188097)
      Nature. 2006 Sep 21;443(7109):289-95. (PMID: 16988703)
      Curr Biol. 2009 Dec 1;19(22):R1046-52. (PMID: 19948145)
      J Anim Sci. 2008 Apr;86(14 Suppl):E36-50. (PMID: 17998426)
      Eur J Neurosci. 2003 Aug;18(4):942-50. (PMID: 12925020)
      Science. 2008 Nov 7;322(5903):963-6. (PMID: 18988856)
      PLoS One. 2012;7(10):e46923. (PMID: 23056530)
      Behav Brain Res. 2008 Jan 25;186(2):168-75. (PMID: 17854921)
      J Comp Neurol. 2004 Feb 16;469(4):581-607. (PMID: 14755537)
      Cancer Res. 2004 Jan 1;64(1):252-61. (PMID: 14729632)
      PLoS One. 2014;9(5):e93691. (PMID: 24787262)
      Circulation. 2002 Oct 29;106(18):2379-84. (PMID: 12403670)
      J Neurosci. 2006 Dec 13;26(50):12977-83. (PMID: 17167087)
      Cancer Chemother Pharmacol. 2010 Mar;65(4):625-39. (PMID: 19784839)
      Psychopharmacology (Berl). 2012 Mar;220(1):183-93. (PMID: 21894483)
      Neurobiol Learn Mem. 2007 Feb;87(2):303-7. (PMID: 17005423)
      Eur Urol. 2011 Apr;59(4):526-40. (PMID: 21277078)
      Neurosci Lett. 2005 Sep 23;386(1):34-9. (PMID: 15978723)
      Neurosci Lett. 2010 Feb 12;470(2):115-20. (PMID: 20045038)
      Cancer Res. 2007 Mar 15;67(6):2408-13. (PMID: 17363557)
      J Clin Oncol. 2008 Apr 1;26(10):1603-10. (PMID: 18332469)
    • Accession Number:
      0 (Antineoplastic Agents)
      9HW64Q8G6G (Everolimus)
      EC 1.9.3.1 (Electron Transport Complex IV)
      EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
      W36ZG6FT64 (Sirolimus)
    • Publication Date:
      Date Created: 20141202 Date Completed: 20150916 Latest Revision: 20181113
    • Publication Date:
      20240104
    • Accession Number:
      PMC4250083
    • Accession Number:
      10.1371/journal.pone.0113533
    • Accession Number:
      25436776