Inhibition of polyamine oxidases by ifenprodil

The inhibition of different polyamine oxidases (PAO) by ifenprodil, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, was studied. Enzyme activity was determined by measuring hydrogen peroxide release after polyamine oxidation. Ifenprodil inhibited copper-dependent PAO from serum and soybean by 55 and 73%, respectively, and flavin adenine dinucleotide-dependent PAO from Amoeba proteus and P388D1 mouse leukaemic cells by 55 and 15%, respectively. As the action of ifenprodil is linked to a reduction of neuronal putrescine, the results suggest that in addition to its effect on the polyamine sites of the NMDA receptor, ifenprodil could regulate the intracellular content of putrescine, a natural polyamine. This could be achieved by inhibition of ornithine decarboxylase, which provides putrescine from ornithine and by inhibiting the retroconversion of higher polyamines (spermine and spermidine) to putrescine, the main source of putrescine in the brain. The inhibition of the PAO also decreases the generation of potentially neurotoxic hydrogen peroxide derived from polyamine oxidation.