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

Abstract

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite β-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.

Phenelzine-based probes reveal Secernin-3 is involved in thermal nociception

“…For example, anti-nociceptive effects of PHZ were observed in models of inflammatory pain (Mifflin et al, 2016), chronic pain (Davidson and Raft, 1985), in allodynia associated with experimental autoimmune encephalomyelitis (EAE) in a mouse model for multiple sclerosis (Potter et al, 2016) and in a clinical study evaluating PHZ for treatment of neuropathic pain in patients with fibromyalgia (Tort et al, 2012). Further, by acting as an aldehyde scavenger, PHZ exhibits neuroprotective effects in Parkinson’s disease and spinal cord contusive injury (MacKenzie et al, 2010; Song et al, 2010; Al-Nuaimi et al, 2012; Chen et al, 2016; Matveychuk et al, 2022), and reduces oxidative damage following traumatic brain injury (Hill et al, 2020). Importantly, PHZ is not addictive (Ananth et al, 1995) and has anti-abuse potential, as clinical studies revealed PHZ reduces tobacco dependence (George and Weinberger, 2008) and cocaine abuse (Golwyn, 1988).…”

Biological Evaluation of Valeriana Extracts from Argentina with Potent Cholinesterase Inhibition for the Treatment of Neurodegenerative Disorders and Their Comorbidities—The Case of Valeriana carnosa Sm. (Caprifoliaceae) Studied in Mice

“…In turn, isatin (indole-2,3-dione) is an endogenous inhibitor of MAO B [ 57 ]. Furthermore, MAO inhibitors inhibit hydrogen peroxide production, which triggers a neuroprotective effect [ 58 ].…”

Roles of selected non-P450 human oxidoreductase enzymes in protective and toxic effects of chemicals: review and compilation of reactions

“…Thus, besides its MAO inhibiting activity, phenelzine also elevates brain levels of γ-aminobutyric acid (GABA) which may also contribute to its anxiolytic effects, and the effects ascribed to the phenelzine intermediate metabolite β-phenylethylidenehydrazine, a weak MAO inhibitor (Baker et al 2019 ; Parent et al 2002 ). Phenelzine may also ameliorate the effects of oxidative stress by reducing the formation of reactive metabolites (aldehydes, hydrogen peroxide, ammonia/ammonia derivatives) produced by the interaction of MAO with biogenic amines, as well as by inhibiting primary amine oxidase (Baker et al 2019 ; Matveychuk et al 2021 ). This example illustrates the complex interactions of the parent drug and its metabolite(s) on the final effects.…”