Background and Methods. In 1987 we began a multicenter controlled clinical trial of deprenyl (a mono-amine oxidase inhibitor) and tocopherol (a component of vitamin E that traps free radicals) in the treatment of early Parkinson's disease. We randomly assigned 800 patients to one of four treatments: placebo, active tocopherol and deprenyl placebo, active deprenyl and tocopherol placebo, or both active drugs. The primary end point was the onset of disability prompting the clinical decision to begin administering levorlopa

Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease

Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.

The therapeutic potential of monoamine oxidase inhibitors.

Deficiency in monoamine oxidase A (MAOA), an enzyme that degrades serotonin and norepinephrine, has recently been shown to be associated with aggressive behavior in men of a Dutch family. A line of transgenic mice was isolated in which transgene integration caused a deletion in the gene encoding MAOA, providing an animal model of MAOA deficiency. In pup brains, serotonin concentrations were increased up to ninefold, and serotonin-like immunoreactivity was present in catecholaminergic neurons. In pup and adult brains, norepinephrine concentrations were increased up to twofold, and cytoarchitectural changes were observed in the somatosensory cortex. Pup behavioral alterations, including trembling, difficulty in righting, and fearfulness were reversed by the serotonin synthesis inhibitor parachlorophenylalanine. Adults manifested a distinct behavioral syndrome, including enhanced aggression in males.

/pdf/aggressive-behavior-and-altered-amounts-of-brain-serotonin-jnp9rmiku2.pdf

Aggressive Behavior and Altered Amounts of Brain Serotonin and Norepinephrine in Mice Lacking MAOA

Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (Xp11.23) and comprise 15 exons with identical intron-exon organization, which suggests that they are derived from the same ancestral gene. MAO A and B knock-out mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A knock-out mice have elevated brain levels of serotonin, norephinephrine, and dopamine and manifest aggressive behavior similar to human males with a deletion of MAO A. In contrast, MAO B knock-out mice do not exhibit aggression and only levels of phenylethylamine are increased. Mice lacking MAO B are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine. Both MAO A and B knock-out mice show increased reactivity to stress. These knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

/pdf/monoamine-oxidase-from-genes-to-behavior-48htyx6r2z.pdf

Monoamine oxidase: from genes to behavior.

We describe a new polymorphism upstream of the gene for monoamine oxidase A (MAOA), an important enzyme in human physiology and behavior. The polymorphism, which is located 1.2 kb upstream of the MAOA coding sequences, consists of a 30-bp repeated sequence present in 3, 3.5, 4, or 5 copies. The polymorphism is in linkage disequilibrium with other MAOA and MAOB gene markers and displays significant variations in allele frequencies across ethnic groups. The polymorphism has been shown to affect the transcriptional activity of the MAOA gene promoter by gene fusion and transfection experiments involving three different cell types. Alleles with 3.5 or 4 copies of the repeat sequence are transcribed 2–10 times more efficiently than those with 3 or 5 copies of the repeat, suggesting an optimal length for the regulatory region. This promoter region polymorphism may be useful as both a functional and an anonymous genetic marker for MAOA.

A functional polymorphism in the monoamine oxidase A gene promoter

Monoclonal antibodies specific for monoamine oxidase (MAO) A and MAO B, respectively, were used to localize these enzymes in primate brain. The reagents recognized different populations of neurons: those that recognized MAO A were located in cell groups containing catecholamines, including the substantia nigra, nucleus locus coeruleus, nucleus subcoeruleus, and the periventricular region of the hypothalamus, whereas those that recognized MAO B were observed in serotonin regions, including the nucleus raphe dorsalis and nucleus centralis superior. These data illustrate the physiological independence of MAO A and B and show that neurons may be specialized for their degradative as well as their synthetic functions.

https://science.sciencemag.org/content/sci/230/4722/181.full.pdf

Distinct monoamine oxidase A and B populations in primate brain.

Localization of distinct monoamine oxidase A and monoamine oxidase B cell populations in human brainstem.

Among fifteen male skin fibroblast cultures from eleven donors ranging in age from less than 1 year to 90 years old, the specific activity of monoamine oxidase A (MAO-A) differed 515-fold. Each culture had one of the two most common alleles (three or four 30-bp repeats) at the variable number tandem repeat locus positioned 1.2 kb upstream from MAOA exon 1 (uVNTR). The mean MAO-A activity in cultures with three uVNTR repeats was significantly lower than that in cultures with four repeats (1.6 +/- 1.1 and 13 +/- 12 nmol/h per milligram, respectively; P=0.032). MAO-A expression was confined to a cell sub-population varying from 0.5% to 90% of cells in different cultures. The mean specific activity in MAO-A+ cells (whole culture specific activity divided by the proportion of immunopositive cells) was lower for cultures with three repeats than for those with four (7.2 +/- 3.1 and 23.9 +/- 9.5 nmol/h per milligram protein, respectively; P=0.0013), with no overlap in activity between genotypes. Finding lower MAO-A activity in cultures with three uVNTR repeats compared to those with four is consistent with published evidence that MAO-A promoter constructs bearing three repeats have lower transcriptional activity in transfected neuroblastoma and choriocarcinoma cells. The uVNTR genotype may be a common genetic determinant of significant individual differences in oxidizing capacity for critical MAO-A substrates, which include serotonin, norepinephrine, and tyramine.

Association between monoamine oxidase A activity in human male skin fibroblasts and genotype of the MAOA promoter-associated variable number tandem repeat.

A monoclonal antibody was used to prepare immunoaffinity columns that efficiently bind monoamine oxidase B activity but not monoamine oxidase A activity from detergent extracts of human liver mitochondria. The only discrete polypeptide component that eluted from affinity columns with potassium thiocyanate migrated in sodium dodecyl sulfate-polyacrylamide gels with an apparent molecular weight of 59,000, as expected for human monoamine oxidase B. These results support the hypothesis that there is an intrinsic structural difference between monoamine oxidase A and B and demonstrate that immunoaffinity chromatography can physically resolve the two enzyme species in liver extracts.

https://science.sciencemag.org/content/sci/215/4538/1400.full.pdf

Richard M. Denney

Papers

Distinct monoamine oxidase A and B populations in primate brain.

Localization of distinct monoamine oxidase A and monoamine oxidase B cell populations in human brainstem.

Association between monoamine oxidase A activity in human male skin fibroblasts and genotype of the MAOA promoter-associated variable number tandem repeat.

Human liver MAO-A and MAO-B separated by immunoaffinity chromatography with MAO-B-specific monoclonal antibody.

Topographic immunocytochemical mapping of monoamine oxidase-A, monoamine oxidase-B and tyrosine hydroxylase in human post mortem brain stem.