title: The Polyphenol Oleuropein Aglycone Modulates the PARP1-SIRT1 Interplay: An In Vitro and In Vivo Study.
abstract: Poly(ADP-ribose) polymerase-1 (PARP1) activation contributes to the cascade of events initiated by amyloid-β (Aβ) peptide eventually leading to cell death in Alzheimer's disease brain. A significant accumulation of PAR polymers and increase of PARP1 expression were detected in the cortex at the early (3.5 months) and intermediate (6 months) stage of Aβ deposition in the TgCRND8 mouse model. Our previous data highlighted the beneficial effects of oleuropein aglycone (OLE), the main polyphenol found in the olive oil, against neurodegeneration both in cultured cells and in model organisms. Here we found that 8-week OLE treatment (50 mg/kg of diet) to 6-month-old TgCRND8 mice rescued to control values PARP1 activation and the levels of its product, PAR. In N2a neuroblastoma cells, PARP1 activation and PAR formation upon exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were abolished by pretreatment for 24 h with either OLE (100μM) or PARP inhibitors. A significant reduction of the NAD+ content, compared to controls, was found in N2a cells exposed to MNNG (100μM) for 90 min; the latter was slightly attenuated by cell treatment for 24 h with PJ-34 or with OLE. In vitro and in vivo, the OLE-induced reduction of PARP1 activation was paralleled by the overexpression of Sirtuin1 (SIRT1), and, in vivo, by a decrease of NF-κB and the pro-apoptotic marker p53. In N2a cells, we also found that OLE potentiates the MNNG-induced increase of Beclin1 levels. In conclusion, our data show that OLE treatment counteracts neuronal damage through modulation of the PARP1-SIRT1 interplay.
authors: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors: Ilaria
authors: I
authors: Luccarini
authors: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors: Daniela
authors: D
authors: Pantano
authors: Department of Experimental Biomedical and Clinical Sciences, University of Florence, Florence, Italy.
authors: Pamela
authors: P
authors: Nardiello
authors: Department of Health Sciences, University of Florence, Florence, Italy.
authors: Leonardo
authors: L
authors: Cavone
authors: Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
authors: Andrea
authors: A
authors: Lapucci
authors: Department of Experimental Biomedical and Clinical Sciences, University of Florence, Florence, Italy.
authors: Caterina
authors: C
authors: Miceli
authors: Department of Experimental Biomedical and Clinical Sciences, University of Florence, Florence, Italy.
authors: Chiara
authors: C
authors: Nediani
authors: Department of Experimental Biomedical and Clinical Sciences, University of Florence, Florence, Italy.
authors: Andrea
authors: A
authors: Berti
authors: Department of Experimental Biomedical and Clinical Sciences, University of Florence, Florence, Italy.
authors: Massimo
authors: M
authors: Stefani
authors: Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
authors: Fiorella
authors: F
authors: Casamenti
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D057888:Iridoid Glucosides; D039823:Iridoids / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D059808:Polyphenols / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D057888:Iridoid Glucosides; D039823:Iridoids; D059808:Polyphenols; D014665:Vasodilator Agents; C002769:oleuropein; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Alzheimer’s disease; PAR polymers; animal model of Aβ deposition; olive oil polyphenols