Attenuation of the effects of oxidative stress by the MAO-inhibiting antidepressant and carbonyl scavenger phenelzine. (1st May 2019)

• Record Type: Journal Article
• Authors: Baker, Glen; Matveychuk, Dmitriy; MacKenzie, Erin M.; Holt, Andrew; Wang, Yanlin; Kar, Satyabrata
• Is Part Of: Chemico-biological interactions. Volume 304(2019)
• Page Start: 139
• Page End: 147
• Publication Date: 2019-05-01
• Subjects: Phenelzine -- Monoamine oxidase -- GABA transaminase -- Reactive aldehydes -- Primary amine oxidase -- Antidepressant; ADAM-10 α-secretase -- AD Alzheimer's disease -- BACE β-secretase -- CCI-TBI controlled cortical impact traumatic brain injury -- DOPAL 3, 4-dihydroxyphenylacetaldehyde -- DOPEGAL 3, 4-dihydroxyphenylglycolaldehyde -- EAE experimental autoimmune encephalomyelitis -- FAD flavin adenine dinucleotide -- GABA γ-aminobutyric acid -- H2O2 hydrogen peroxide -- HNE 4-hydroxy-2-nonenal -- 5-HT 5-hydroxytryptamine (serotonin) -- MAO monoamine oxidase -- MPP+ 1-methyl-4-phenylpyridinium -- MPTP 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine -- PD Parkinson's disease -- PEH β-phenylethylidenehydrazine -- PrAO primary amine oxidase -- RNS reactive nitrogen species -- ROS reactive oxygen species -- SSAO semicarbazide-sensitive amine oxidase -- SCI spinal cord injury -- TRPA1 transient receptor potential ankyrin 1; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2019.03.003
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Phenelzine (β-phenylethylhydrazine) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. It possesses a number of important pharmacological properties which may alter the effects of oxidative stress. After conducting a comprehensive literature search, the authors of this review paper aim to provide an overview and discussion of the mechanisms by which phenelzine may attenuate oxidative stress. It inhibits γ-aminobutyric acid (GABA) transaminase, resulting in elevated brain GABA levels, inhibits both MAO and primary amine oxidase and, due to its hydrazine-containing structure, reacts chemically to sequester a number of reactive aldehydes (e.g. acrolein and 4-hydroxy-2-nonenal) proposed to be implicated in oxidative stress in a number of neurodegenerative disorders. Phenelzine is unusual in that it is both an inhibitor of and a substrate for MAO, the latter action producing at least one active metabolite, β-phenylethylidenehydrazine (PEH). This metabolite inhibits GABA transaminase, is a very weak inhibitor of MAO but a strong inhibitor of primary amine oxidase, and sequesters aldehydes. Phenelzine may ameliorate the effects of oxidative stress by reducing formation of reactive metabolites (aldehydes, hydrogen peroxide, ammonia/ammonia derivatives) produced by the interaction of MAO with biogenic amines, by sequestering various other reactive aldehydes and by inhibiting primary amine oxidase. In PC12 cells treated with the neurotoxin MPP +, phenelzine has been reported to reduce several adverse effects of MPP + . It has also been reported to reduce lipid peroxidative damage induced in plasma and platelet proteins by peroxynitrite. In animal models, phenelzine has a neuroprotective effect in global ischemia and in cortical impact traumatic brain injury. Recent studies reported in the literature on the possible involvement of acrolein in spinal cord injury and multiple sclerosis indicate that phenelzine can attenuate adverse effects of acrolein in these models. Results from studies in our laboratories on effects of phenelzine and PEH on primary amine oxidase (which catalyzes formation of toxic aldehydes and is overexpressed in Alzheimer's disease), on sequestration of the toxic aldehyde acrolein, and on reduction of acrolein-induced toxicity in mouse cortical neurons are also reported. Highlights: The antidepressant phenelzine reduces several adverse effects of oxidative stress. It acts through inhibition of MAO and PrAO and through scavenging reactive aldehydes. These actions may be relevant to treating several neurodegenerative disorders. Its metabolite PEH is also a strong inhibitor of PrAO and scavenges aldehydes.