Monoamine oxidase inactivation: from pathophysiology to therapeutics

Abstract

Monoamine oxidases (MAOs) A and B are mitochondrial bound isoenzymes which catalyze the oxidative deamination of dietary amines and monoamine neurotransmitters, such as serotonin, norepinephrine, dopamine, beta-phenylethylamine and other trace amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional behaviors and other brain functions. The byproducts of MAO-mediated reactions include several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence, it is widely speculated that prolonged excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances. In keeping with these premises, the development of MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders, ranging from mood disorders to Parkinson's disease. Furthermore, the characterization of MAO knockout (KO) mice has revealed that the inactivation of this enzyme produces a number of functional and behavioral alterations, some of which may be harnessed for therapeutic aims. In this article, we discuss the intriguing hypothesis that the attenuation of the oxidative stress induced by the inactivation of either MAO isoform may contribute to both antidepressant and antiparkinsonian actions of MAO inhibitors. This possibility further highlights MAO inactivation as a rich source of novel avenues in the treatment of mental disorders.

Figure 1. Synaptic processing of serotonin (5-HT)

Following release, 5-HT receptor activation and reuptake by 5-HT transporter (5-HTT), serotonin is degraded by MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) into 5-hydroxyindole-3-acetic acid (5-HIAA).

Figure 2. Synaptic processing of norepinephrine (NE)

Following release, NE receptor activation and reuptake by NE transporter (NET), NE is degraded by three main enzymatic pathways. (1) In the first pathway, MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) convert NE into 3,4-dihydroxymandelic acid (DHMA); this compound is then processed by catechol-O-methyltransferase (COMT) into vanillylmandelic acid (VMA). (2) In the second pathway, MAO and ALR (aldehyde reductase) convert NE into 3,4-dihyroxyphenylglycol (DHPG), which is further degraded by COMT into 3-methoxy-4-hydroxyphenylglycol (MHPG). (3) In the third pathway, COMT metabolizes NE into normetanephrine (NM), which is then converted into either MHPG (via MAO/ALR) or VMA (via MAO/ALDH).

Figure 3. Synaptic processing of dopamine (DA)

Following release, DA receptor activation and reuptake by DA transporter (DAT), DA is degraded by two main enzymatic pathways. (1) In the first pathway, MAO (monoamine oxidase) and ALDH (aldehyde dehydrogenase) convert DA into 3,4-dihydroxyphenylacetic acid (DOPAC); this compound is then processed by catechol-O-methyltransferase (COMT) into homovanillic acid (HVA). (2) In the second pathway, COMT metabolizes DA into 3-methoxytyramine (3-MT), which is then converted into HVA by MAO and ALDH.

Figure 4. MAO catalyzes the oxidative deamination of monoamines

Monoamines are degraded by MAO to their correspondent aldehydes (R-CHO). This reaction produces also ammonia (NH₃) and hydrogen peroxide (H₂O₂). Aldehydes are further oxidized by aldehyde dehydrogenase (ALDH) into carboxylic acids (R-COOH). NADH is a critical cofactor for this latter reaction.