title: The antineoplastic drug flavopiridol reverses memory impairment induced by Amyloid-ß1-42 oligomers in mice.
abstract: The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer's disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of Aß1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of Aβ-injected mice, paralleling memory deficits. Starting from three days after Aβ injection, flavopiridol (0.5, 1 and 3mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1mg/kg) was able to rescue the loss of memory induced by Aβ1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Leggio
authors.affiliation: National Research Council, Institute of Neurological Sciences (ISN-CNR), Catania, Italy; IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, EN, Italy.
authors.forename: Maria Vincenza
authors.initials: MV
authors.lastname: Catania
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Puzzo
authors.affiliation: National Research Council, Institute of Neurological Sciences (ISN-CNR), Catania, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Spatuzza
authors.affiliation: National Research Council, Institute of Neurological Sciences (ISN-CNR), Catania, Italy.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Pellitteri
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Gulisano
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Sebastiano Alfio
authors.initials: SA
authors.lastname: Torrisi
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Giurdanella
authors.affiliation: Pharmacokinetic Unit, Unifarm Research Center, Catania, Italy.
authors.forename: Cateno
authors.initials: C
authors.lastname: Piazza
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Agata Rita
authors.initials: AR
authors.lastname: Impellizzeri
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gozzo
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Navarria
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; Pharmacokinetic Unit, Unifarm Research Center, Catania, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bucolo
authors.affiliation: IRCCS Neuromed, Pozzilli IS, Italy; Department of Physiology and Pharmacology, University of Rome Sapienza, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Palmeri
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; Pharmacokinetic Unit, Unifarm Research Center, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
authors.affiliation: National Research Council, Institute of Biostructure and Bioimaging (IBB-CNR), Catania, Italy; Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Copani
authors.affiliation: IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, EN, Italy; Department of Drug Sciences, University of Catania, Catania, Italy. Electronic address: carafil@hotmail.com.
authors.forename: Filippo
authors.initials: F
authors.lastname: Caraci
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000009:adverse effects*; D010880:Piperidines / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D000970:Antineoplastic Agents; D005419:Flavonoids; D010446:Peptide Fragments; D010880:Piperidines; C077990:alvocidib; D018844:Cyclin-Dependent Kinases
keywords: Alzheimer’s disease; Cell cycle; Flavopiridol; Flavopiridol (PubChem CID: 9910986); Memory deficit; Oligomers; β-amyloid