title: Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1-42)-induced toxicity.
abstract: Monoamine oxidase (MAO) enzymes play a central role in the pathogenesis of Alzheimer's disease (AD) and MAO inhibitors (MAOIs) are antidepressant drugs currently studied for their neuroprotective properties in neurodegenerative disorders. In the present work MAOIs such as tranylcypromine [trans-(+)-2-phenylcyclopropanamine, TCP] and its amide derivatives, TCP butyramide (TCP-But) and TCP acetamide (TCP-Ac), were tested for their ability to protect cortical neurons challenged with synthetic amyloid-β (Aβ)-(1-42) oligomers (100 nM) for 48 h. TCP significantly prevented Aβ-induced neuronal death in a concentration-dependent fashion and was maximally protective only at 10 µM. TCP-But was maximally protective in mixed neuronal cultures at 1 µM, a lower concentration compared to TCP, whereas the new derivative, TCP-Ac, was more efficacious than TCP and TCP-But and significantly protected cortical neurons against Aβ toxicity at nanomolar concentrations (100 nM). Experiments carried out with the Thioflavin-T (Th-T) fluorescence assay for fibril formation showed that TCP and its amide derivatives influenced the early events of the Aβ aggregation process in a concentration-dependent manner. TCP-Ac was more effective than TCP-But and TCP in slowing down the Aβ(1-42) aggregates formation through a lengthening at the lag phase. In our experimental model co-incubation of Aβ(1-42) oligomers with TCP-Ac was able to almost completely prevent Aβ-induced neurodegeneration. These results suggest that inhibition of Aβ oligomer-mediated aggregation significantly contributes to the overall neuroprotective activity of TCP-Ac and also raise the possibility that TCP, and in particular the new compound TCP-Ac, might represent new pharmacological tools to yield neuroprotection in AD.
authors.affiliation: Department of Drug Sciences, University of Catania, Catania, Italy; IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, Troina, Italy. Electronic address: carafil@hotmail.com.
authors.forename: Filippo
authors.initials: F
authors.lastname: Caraci
authors.affiliation: National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pappalardo
authors.affiliation: Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Basile
authors.affiliation: National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giuffrida
authors.affiliation: Department of Drug Sciences, University of Catania, Catania, Italy; National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy.
authors.forename: Agata
authors.initials: A
authors.lastname: Copani
authors.affiliation: National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Tosto
authors.affiliation: National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy; PhD Program in Translational Biomedicine, University of Catania, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sinopoli
authors.affiliation: National Research Council, Institute of Biostructures and Bioimaging, Catania, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giuffrida
authors.affiliation: Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Pirrone
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Drago
authors.affiliation: Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Pignatello
authors.affiliation: Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
mesh_terms: D000577:Amides / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D051381:Rats; D014191:Tranylcypromine / Q000494:pharmacology*
chemical_list: D000577:Amides; D016229:Amyloid beta-Peptides; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D014191:Tranylcypromine
keywords: Amyloid; Anti-aggregant activity; Antidepressants; Butyric acid (PubChem CID: 264); MAO; Neurons; Neuroprotection; Tranylcypromine (PubChem CID: 19493 or 26070); Tranylcypromine acetamide (PubChem CID: 583384)