Monoamine oxidase inhibition and neuroprotection by N1‐propargylphenelzine

Abstract

AbstractThe ability of N1‐propargylphenelzine and related N1‐propargylhydrazines to inhibit monoamine oxidase‐A (MAO‐A) and ‐B (MAO‐B) and to prevent N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP‐4)‐induced noradrenergic neurotoxicity was examined. N1‐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 N1‐propargylphenelzine strongly inhibited brain and liver MAO‐A and MAO‐B. The extent of ex vivo MAO inhibition and increased levels of noradrenaline and 5‐hydroxytryptamine by N1‐propargylphenelzine was comparable to that of phenelzine. Unlike phenelzine, however, N1‐propargylphenelzine did not elevate γ‐aminobutryic acid (GABA) concentrations in rat brain. A single intraperitoneal administration of N1‐propargylphenelzine to mice, 1 week prior to sacrifice, reduced DSP‐4‐induced depletion of noradrenaline in the hippocampus. The brains of N1‐propargylphenelzine‐treated mice from the DSP‐4 neurotoxicity experiments had normal MAO‐B activity, but MAO‐A was significantly inhibited; this was in contrast to animals that had received (–)‐deprenyl, who showed normal MAO‐A activity but a decrease of MAO‐B. The present results indicate that N1‐propargylphenelzine may be a useful neuroprotective compound with a long‐term in vivo propensity to inhibit MAO‐A. Drug Dev. Res. 53:15–21, 2001. © 2001 Wiley‐Liss, Inc.