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

Dmitriy Matveychuk,Mee-Sook Song,Glen B Baker,Satyabrata Kar,David Kumpula,Andrew Holt,Erin M Mackenzie,Paul L Wood,Kathryn G Todd

doi:10.1007/s10571-021-01078-3

Dmitriy Matveychuk, Mee-Sook Song + Show 7 more

Open Access

https://doi.org/10.1007/s10571-021-01078-3

Copy DOI

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.

Highlights

In the last 25 years, numerous exciting research reports have demonstrated that many antidepressants and antipsychotics have neuroprotective and/or neurorescue properties (Baker et al 2012; Chen and Nasrallah 2019; Hunsberger et al 2009; Li and Xu 2007; Lieberman et al 2008; Shadfar et al 2018; Song et al 2013; Sowa et al 2004; Tatton et al 2003; Xu et al 2003; Youdim and Bakhle 2006; Young 2002)
The following aspects which appear to be contributing to the neuroprotective effects of PLZ will be discussed in detail in this review: contribution of an active metabolite; inhibition of monoamine oxidase (MAO); inhibition of γ-aminobutyric acid transaminase (GABA-T) and elevation of brain GABA levels; elevation of brain levels of the amino acid ornithine and N-acetylamino acids; sequestration of toxic reactive aldehydes such as formaldehyde, acrolein, 3-aminopropanal, malondialdehyde, and 4-hydroxy-2-nonenal (4-HNE); and inhibition of primary amine oxidase [Primary Amine Oxidase (PrAO), known as semicarbazide-sensitive amine oxidase (SSAO)]
In 1969 Popov and Matthies reported that the treatment of rats with another monoamine oxidase inhibitors (MAOIs) before administering PLZ attenuated the ability of PLZ to elevate brain levels of GABA, suggesting that a metabolite formed by the action of MAO on PLZ was responsible for the observed effects

Summary

Introduction

In the last 25 years, numerous exciting research reports have demonstrated that many antidepressants and antipsychotics have neuroprotective and/or neurorescue properties (Baker et al 2012; Chen and Nasrallah 2019; Hunsberger et al 2009; Li and Xu 2007; Lieberman et al 2008; Shadfar et al 2018; Song et al 2013; Sowa et al 2004; Tatton et al 2003; Xu et al 2003; Youdim and Bakhle 2006; Young 2002). PEH is only a weak inhibitor of MAO (MacKenzie et al 2008a; Matveychuk 2015; Matveychuk et al 2013; Paslawski et al 2001), it has several actions, including effects on brain levels of GABA, sequestration of reactive aldehydes, and inhibition of PrAO that may contribute to the neuroprotective/neurorescue properties of PLZ, and these actions will be described in the appropriate sections below.

Results

Conclusion