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Permanent link (DOI): https://doi.org/10.7939/R3FT8DQ4H

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Novel properties of the multifaceted drug phenelzine and its metabolite β-phenylethylidenehydrazine Open Access

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Other title
Subject/Keyword
tyrosine
monoamine oxidase
amino acids
phenelzine
reactive aldehydes
neuroprotection
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Matveychuk, Dmitriy
Supervisor and department
Baker, Glen B. (Psychiatry)
Examining committee member and department
Siraki, Arno G. (Pharmacy and Pharmaceutical Sciences)
Dursun, Serdar M. (Psychiatry)
Kar, Satyabrata (Psychiatry)
Kong, Jiming (Human Anatomy and Cell Science)
Department
Department of Psychiatry
Specialization
Psychopharmacology
Date accepted
2015-08-10T11:32:04Z
Graduation date
2015-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Phenelzine is a monoamine oxidase (MAO) inhibitor that has been used for the treatment of depression and anxiety disorders since the 1960s. In recent years, there has been renewed interest in this drug following reports of its neuroprotective properties in animal models of cerebral ischemia, multiple sclerosis and traumatic brain injury. It has been suggested that phenelzine is metabolized to an active metabolite, namely β-phenylethylidenehydrazine (PEH), by the action of MAO. PEH appears to share some of the neuroprotective properties of phenelzine and may be an interesting new drug in its own right. The work presented in this thesis has investigated the neurochemical effects of phenelzine and PEH and discussed these findings with regard to neuroprotection. First of all, the metabolism of phenelzine by human MAO-B was examined: this has included confirmation that PEH is a major product of phenelzine oxidation by the enzyme in vitro, studies examining the rate of PEH hydrolysis in aqueous media and elucidation of the mechanisms of MAO-B inhibition by phenelzine. Moreover, the effects of phenelzine and geometric isomers of PEH, (E)- and (Z)-PEH, on rat whole brain levels of amino acids, biogenic amine neurotransmitters and methylamine were compared. Both (E)- and (Z)-PEH appeared to be equivalent in their neurochemical properties under the conditions used in this study. Phenelzine and the PEH isomers produced marked increases in rat brain levels of γ-aminobutyric acid (GABA) and alanine while reducing levels of glutamine. Phenelzine, but neither PEH isomer, considerably elevated rat brain levels of serotonin, noradrenaline and dopamine. Rat brain levels of methylamine, a substrate for primary amine oxidase (PrAO), were elevated for all three drugs; however, the effect of phenelzine on methylamine was more transient in comparison to both PEH isomers. These findings provide support for the ability of phenelzine and PEH to inhibit PrAO, an enzyme that catalyzes the formation of toxic aldehydes and whose activity and expression have been reported to be increased in Alzheimer’s disease, in the rat brain. In addition, administration of both PEH isomers and phenelzine resulted in dramatic increases in rat whole brain tyrosine levels. It appears that the tyrosine-elevating property of phenelzine is mediated by PEH, as pre-treatment with another MAO inhibitor abolished the effect of phenelzine, but not of PEH, on brain tyrosine levels. Furthermore, phenelzine and PEH were effective at sequestering the toxic reactive aldehydes acrolein, malondialdehyde and methylglyoxal in vitro. In mouse cortical neurons, phenelzine and PEH attenuated acrolein-induced toxicity in a dose-dependent manner. However, neither phenelzine nor PEH reduced rat whole brain levels of extractable acrolein; phenelzine, but not PEH, reduced rat whole brain malondialdehyde levels. The findings presented in this thesis suggest that phenelzine and PEH possess several properties that may be relevant to neuroprotection. As such, they may prove to be useful adjunctive drugs in the treatment of numerous neurological disorders, such as cerebral ischemia, epilepsy, Alzheimer’s and Parkinson’s diseases. Further investigation of phenelzine and PEH with regard to application in these disorders is warranted.
Language
English
DOI
doi:10.7939/R3FT8DQ4H
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Matveychuk, D., Nunes, E., Ullah, N. Velázquez-Martinez, C.A., MacKenzie, E.M. and Baker, G.B. Comparison of phenelzine and geometric isomers of its active metabolite, β-phenylethylidenehydrazine, on rat brain levels of amino acids, biogenic amine neurotransmitters and methylamine. Journal of Neural Transmission 2013; 120(6): 987-996.Matveychuk, D., Nunes, E., Ullah, N. Aldawsari, F. S., Velázquez-Martinez, C.A. and Baker, G.B. Elevation of rat brain tyrosine levels by phenelzine is mediated by its active metabolite β-phenylethylidenehydrazine. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53: 67-73.Matveychuk, D., Dursun, S. M., Wood, P.L. and Baker, G.B. Reactive aldehydes and neurodegenerative disorders. Bulletin of Clinical Psychopharmacology 2011; 21(4): 277-288.

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