title: Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-β 1-42 induced neurotoxicity and memory impairment.
abstract: Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the main cause of dementia. Substantial evidences indicate that there is over-activation of the PI3K/Akt/mTOR axis in AD. Therefore, the aim of the present study was to investigate the effects of NVP-BEZ235 (BEZ; dactolisib), a dual PI3K/mTOR inhibitor that is under phase I/II clinical trials for the treatment of some types of cancer, in hippocampal neuronal cultures stimulated with amyloid-β (Aβ) 1-42 and in mice injected with Aβ 1-42 in the hippocampus. In cell cultures, BEZ reduced neuronal death induced by Aβ. BEZ, but not rapamycin, a mTOR inhibitor, or LY294002, a PI3K inhibitor that also inhibits mTOR, reduced the memory impairment induced by Aβ. The effect induced by Aβ was also prevented in PI3Kγ(-/-) mice. Neuronal death and microgliosis induced by Aβ were reduced by BEZ. In addition, the compound increased IL-10 and TNF-α levels in the hippocampus. Finally, BEZ did not change the phosphorylation of Akt and p70s6K, suggesting that the involvement of PI3K and mTOR in the effects induced by BEZ remains controversial. Therefore, BEZ represents a potential strategy to prevent the pathological outcomes induced by Aβ and should be investigated in other models of neurodegenerative conditions.
authors.affiliation: Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.
authors.forename: Paula Maria Quaglio
authors.initials: PM
authors.lastname: Bellozi
authors.affiliation: Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.
authors.forename: Isabel Vieira de Assis
authors.initials: IV
authors.lastname: Lima
authors.affiliation: Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.
authors.forename: Juliana Guimarães
authors.initials: JG
authors.lastname: Dória
authors.affiliation: Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Brazil.
authors.forename: Érica Leandro Marciano
authors.initials: ÉL
authors.lastname: Vieira
authors.affiliation: Department of Pharmacology, Universidade de São Paulo, Ribeirão Preto, 14049-900, Brazil.
authors.forename: Alline Cristina
authors.initials: AC
authors.lastname: Campos
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Candelario-Jalil
authors.affiliation: Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.
authors.forename: Helton José
authors.initials: HJ
authors.lastname: Reis
authors.affiliation: Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, 30130-100, Brazil.
authors.forename: Antônio Lúcio
authors.initials: AL
authors.lastname: Teixeira
authors.affiliation: Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.
authors.forename: Fabíola Mara
authors.initials: FM
authors.lastname: Ribeiro
authors.affiliation: Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.
authors.forename: Antônio Carlos Pinheiro
authors.initials: AC
authors.lastname: de Oliveira
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology*; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D008569:Memory Disorders / Q000517:prevention & control*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D007093:Imidazoles; D018696:Neuroprotective Agents; D011804:Quinolines; C531198:dactolisib