Monoamine oxidase inhibition and neuroprotection by N-1-propargylphenelzine

The ability of N-1-propargylphenelzine and related N-1-propargylhydrazines to inhibit monoamine oxidase-A (MAO-A) and -B (MAO-B) and to prevent N-(2-c hloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)-induced noradrenergic neurot oxicity was examined. N-1-Propargylphenelzine strongly inhibited MAO-A and MAO-B in in vitro assays using rat brain or liver as the enzyme source. In ex vivo studies in rats, both intraperitoneal and oral administration of N- 1-propargylphenelzine strongly inhibited brain and liver MAO-A and MAO-B. T he extent of ex vivo MAO inhibition and increased levels of noradrenaline a nd 5-hydroxytryptamine by N-1-propargylphenelzine was comparable to that of phenelzine. Unlike phenelzine, however, N-1-propargylphenelzine did not el evate gamma -aminobutryic acid (GABA) concentrations in rat brain. A single intraperitoneal administration of N-1-propargylphenelzine to mice, 1 week prior to sacrifice, reduced DSP-4-induced depletion of noradrenaline in the hippocampus. The brains of N-1-propargylphenelzine-treated mice from the D SP-4 neurotoxicity experiments had normal MAO-B activity, but MAO-A was sig nificantly inhibited; this was in contrast to animals that had received (-) -deprenyl, who showed normal MAO-A activity but a decrease of MAO-B. The pr esent results indicate that N-1-propargylphenelzine may be a useful neuropr otective compound with a long-term in vivo propensity to inhibit MAO-A. (C) 2001 Wiley-Liss, Inc.