Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1-42)-induced toxicity

Filippo Caraci, Giuseppe Pappalardo, Livia Basile, Alessandro Giuffrida, Agata Copani, Rita Tosto, Alessandro Sinopoli, Maria Laura Giuffrida, Emanuele Pirrone, Filippo Drago, Rosario Pignatello, Salvatore Guccione

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Abstract

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.

Original languageEnglish
Article number70113
Pages (from-to)256-263
Number of pages8
JournalEuropean Journal of Pharmacology
Volume764
DOIs
Publication statusPublished - Jul 18 2015

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Keywords

  • Amyloid
  • Anti-aggregant activity
  • Antidepressants
  • MAO
  • Neurons
  • Neuroprotection

ASJC Scopus subject areas

  • Pharmacology

Cite this

Caraci, F., Pappalardo, G., Basile, L., Giuffrida, A., Copani, A., Tosto, R., Sinopoli, A., Giuffrida, M. L., Pirrone, E., Drago, F., Pignatello, R., & Guccione, S. (2015). Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1-42)-induced toxicity. European Journal of Pharmacology, 764, 256-263. [70113]. https://doi.org/10.1016/j.ejphar.2015.07.015