Metabolomics of Rat Brain After Treatment with Phenelzine: High-Resolution Mass Spectrometric Demonstration of Increased Brain Levels of N-Acetyl Amino Acids

Abstract

Background: Phenelzine (PLZ) is a non-specific monoamine oxidase inhibitor that has demonstrated clinical efficacy in patients with treatment resistant depression. The mechanism of action with regard to this efficacy is complicated in that its metabolite, β-phenylethylidenehydrazine (PEH), is an inhibitor of amino acid transaminases resulting in dramatic brain elevations of GABA, alanine, ornithine and tyrosine. The full neurochemical profile of PLZ and PEH remain to be explored. Objective: To undertake a non-targeted metabolomics study of phenelzine on rat brain neurochemistry. Methods: We undertook a high-resolution mass spectrometric metabolomics analysis of rat cortical brain 1 and 12 hours after intraperitoneal dosing with PLZ or PEH. Tandem mass spectrometry was utilized to obtain relative quantitation data. Results: N-acetyl amino acids were found to be elevated in cortical brain tissue following either PLZ or PEH treatments. Conclusions: Our data indicate PLZ treatment significantly augments brain levels of N-acetyl amino acids and that this may involve inhibition of deacylases by PEH and/or induction of N-amino acid acetyltransferases.

Overview of the Neuroprotective Effects of the MAO-Inhibiting Antidepressant Phenelzine

“…In metabolomics studies, we also found that ip treatment of male rats with PLZ or PEH resulted in marked increases in brain cortex levels of ornithine (MacKenzie et al 2008b ) and a number of N-acetylated amino acids (Wood et al 2020 ). We speculated that the increased ornithine levels may be an indicator of decreased formation of glutamate and/or polyamines (resulting in decreased formation of reactive aldehydes such as acrolein and 3-AP), thus contributing to neuroprotection.…”