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

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 theft 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-beta (A beta)-(1-42) oligomers (100 nM) for 48 h. TCP significantly prevented A beta-induced neuronal death in a concentration-dependent fashion and was maximally protective only at 10 mu M. TCP-But was maximally protective in mixed neuronal cultures at 10 mu M, 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 A beta 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 A beta aggregation process in a concentration-dependent manner. TCP-Ac was more effective than TCP-But and TCP in slowing down the A beta (1-42) aggregates formation through a lengthening at the lag phase. In our experimental model coincubation of A beta(1-42) oligomers with TCP-Ac was able to almost completely prevent A beta-induced neurodegeneration. These results suggest that inhibition of A beta oligomenmediated 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. (C) 2015 Elsevier B.V. All rights reserved.