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PubMed1981

Monoamine oxidase in brain maturation: a histochemical study during posthatching development in altricial birds.

Monoamine oxidase was studied histochemically in the brain of three altricial birds, domestic pigeon house swift and house sparrow, during posthatching development. It was found that there was a steady increase in the activity of the enzyme in all areas of the brain of the three birds. The medulla and thalamus showed adult pattern of maturation by 15-20 days in sparrow while the optic lobes and cerebellum did so by 25 days in the former and 11 days in the latter. The cerebral hemispheres showed this by 25-30 days in pigeon and swift and 14 days in sparrow. The hind brain regions showed maximum activity followed by optic lobes, cortex, basal ganglia and cerebellum. The development of the enzyme activity coincided with myelination, in the different areas, as well as with the development of other mitochondrial enzymes. The study indicates that the maturation of the monoaminergic neurotransmitter systems occurs by 30 days in pigeon and swift, while it takes only about half that time i.e., 14 days, in sparrow.

Aging↗

PubMed1986

A comparison of platelet monoamine oxidase activity and phosphatidylserine content between chronic paranoid schizophrenics and normal controls.

Mitochondrial monoamine oxidase (MAO), type B, has been implicated in the etiology of schizophrenia. We have found the phospholipid, phosphatidylserine (PS) to be a highly specific inhibitor of MAO-B, which has led us to postulate that the PS-MAO interaction might offer a basis for the lower MAO levels observed in platelets from certain schizophrenic populations. In this study we compared platelet MAO activity with phospholipid composition in a group of normals and chronic paranoid schizophrenics. The phospholipids in platelets and erythrocytes were extracted and separated by high-performance liquid chromatography into major classes phosphatidylcholine (PC), phosphatidylethanolamine, lysophosphatidylethanolamine, phosphatidylinositol and PS. The paranoid subjects showed statistically significantly lower MAO activity as well as higher mean levels of PS and lower levels of PC in both platelets and erythrocytes, consistent with our hypothesis. The Ca2+-stimulated synthesis of serine-lipid in platelets was also monitored by incorporation of radioisotope into lipid extracts from 14C-labelled serine substrate, and no significant differences were found between subjects groups with respect to this parameter.

Blood Platelets↗

PubMed1980

Differential changes in monoamine oxidase A and B activity in the aging rat brain.

The activity of monoamine oxidase (MAO) was assayed in the brains of young adult (7-8 weeks old) and aging (95-104 weeks old) male Sprague-Dawley rats. When expressed per milligramme of tissue, total protein content was increased to a similar extent in whole brain and in all seven brain regions of the aging rat, whereas MAO A activity (assayed by using 5-hydroxytryptamine as substrate) was unchanged in whole brain but increased in the cerebellum, and fell in the brainstem, midbrain, hippocampus, and cortex; and MAO B activity (assayed by using beta-phenylethylamine as substrate) increased in whole brain and all regions, except the brainstem. Age-related changes in total protein, MAO A and MAO B were thus independent of each other. Kinetic studies indicated that the Vmax of MAO B was increased in aging rat brain, whereas the Km was unaltered. The increase in MAO B activity was restricted to the extrasynaptosomal mitochondrial fraction of the aging brain, whereas a reduction in MAO A activity was found in the intrasynaptosomal, but not the extrasynaptosomal mitochondrial fraction.

Aging↗

PubMed1998

Chronic TVP-1012 (rasagiline) dose--activity response of monoamine oxidases A and B in the brain of the common marmoset.

The stereospecific form of the known acetylenic mechanism-based MAO-inhibitor AGN1135 (Rasagiline, TVP-1012) is devoid of sympathomimetic amphetamine-like properties. To evaluate the efficiency and selectivity of subcutaneous injections of TVP-1012 (dose range from 0.01 up to 10 mg/kg for 7 days) the activities of monoamine oxidases A and B (MAO-A,-B) were determined in different brain regions of the common marmoset. At a dose of 0.1 mg/kg TVP-1012, almost 80% of MAO-B activity is inhibited in all brain regions investigated (prefrontal and occipital cortex, cerebellum, caudate nucleus, putamen, nucleus accumbens). In contrast, MAO-A is not inhibited in putamen and nucleus accumbens. However, by increasing the TVP-1012 dose to 0.5 mg/kg, MAO-A is inhibited to a significant extent as well, concomitant to total inhibition of MAO-B. The results obtained indicate that TVP-1012 irreversibly inhibits both types of MAO in the common marmoset with selectivity for MAO-B at doses less than 0.5 mg/kg. TVP-1012 could be useful in studies requiring selective MAO-B inhibition without concomitant sympathomimetic amphetamine-like effects and could thus be of therapeutic interest for Parkinson's disease and retarded depression.

Animals↗

PubMed2000

Antioxidant activity of the monoamine oxidase B inhibitor lazabemide.

Free radical-induced damage to lipid and protein constituents of neuronal membranes contributes to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). The development of an effective inhibitor of oxidative stress represents an important goal for the treatment of AD. In this study, the intrinsic antioxidant activity of lazabemide, a potent and reversible inhibitor of monoamine oxidase B (MAO-B), was tested in a membrane-based model of oxidative stress. Under physiologic-like conditions, lazabemide inhibited lipid peroxidation in a highly concentration-dependent manner. At low, pharmacologic levels of lazabemide (100.0 nM), there was a significant (P < 0.001) and catalytic reduction in lipid peroxide formation, as compared with control samples. The antioxidant activity of lazabemide was significantly more effective than that of either vitamin E or the MAO-B inhibitor, selegiline. The ability of lazabemide to inhibit oxidative damage is attributed to physico-chemical interactions with the membrane lipid bilayer, as determined by small angle x-ray diffraction methods. By partitioning into the membrane hydrocarbon core, lazabemide can inhibit the propagation of free radicals by electron-donating and resonance-stabilization mechanisms. These findings indicate that lazabemide is a potent and concentration-dependent inhibitor of membrane oxy-radical damage as a result of inhibiting membrane lipid peroxidation, independent of MAO-B interactions.

Animals↗

PubMedDate not supplied

[Comparative characteristics of membrane bound and cytoplasmic monoamine oxidases in human placenta].

Catalytic and physico-chemical properties of human placental monoamine oxidases (MAO) were studied. Both forms of the enzyme, membrane-bound and soluble, exhibited similar properties: optimal activity at pH8.3, equal rate of inhibition with selective MAO inhibitors, identical substrate specificity (the best substrate--serotonin). Some specific differences were found only for cytoplasmic (soluble) MAO: lower affinity for substrates as compared with membrane-bound enzymes, reversible interaction with an inhibitor Lilly 51641 even after long-term preincubation, whereas the mitochondrial MAO bound Lilly 51641 irreversibly. The property of cytoplasmic MAO to form aggregates during storage and/or in gel filtration and concentration did not affect the main catalytic properties of soluble enzyme. Analysis of isoenzyme spectra of membrane-bound and cytoplasmic MAO by means of selective inhibitors and electrophoresis showed that MAO of the two types--A and B were detected in all the subcellular fractions studied. Subunits of MAO of the A type had molecular masses 62, 61 and 61 kDa and of MAO of the B type--51, 55 and 55 kDa in mitochondria, microsomes and cytosol, respectively.

Catalysis↗

PubMed1997

Platelet monoamine oxidase activity as a biological marker in a Swedish forensic psychiatric population.

Platelet monoamine oxidase (MAO) activities were determined in 58 non-psychotic males at forensic psychiatric examinations. The aim of the study was to investigate the role of platelet MAO activity as a biological marker in forensic psychiatry, a clinical field with growing need of safe predictors for both treatment outcome and behavior. The study population was heterogeneous with respect to clinical and personality disorders and personality traits. The results confirmed the role of platelet MAO activity as a biological marker for stable personality traits such as impulsiveness, monotony avoidance and aggressiveness. Disorders with high frequencies of these personality traits such as borderline personality disorder and type II alcoholism could secondarily be associated with low levels of platelet MAO activity, whereas no such associations could be found regarding other clinical or personality disorders. Neither psychopathy as assessed by the means of PCL-R nor behavior such as abuse or criminality could be associated with platelet MAO activity. The conclusion is that, due to its close relationship with stable personality traits, platelet MAO activity serves a marker for vulnerability also in forensic psychiatric populations. On the other hand it is not a marker for clinical or personality disorders, or behavior per se.

Adult↗

PubMed1987

Prevalence of low monoamine oxidase function in alcoholism.

Several studies have found a trend for low platelet monoamine oxidase activity (MAO) in alcoholism but with a great deal of overlap in MAO activity of alcoholics versus controls. The main objective of this study was to carry out a detailed assessment of MAO function that included the measurement of key kinetic parameters (i.e., Km, Vmax) in three groups of male subjects: (a) 51 hospitalized chronic alcoholics, (b) 16 recovering alcoholics with 2-10 years of abstinence, and (c) 21 controls. MAO activity was assayed radiochemically with [14C]tyramine as substrate (43-729 microM). The present study demonstrated that alcoholics had low platelet MAO activity (p less than 0.05). Kinetic analysis revealed a substantial reduction (p less than 0.01) in enzyme Vmax values of chronic and recovering alcoholics. Greater than 95% of the alcoholics had Vmax values lower than the smallest value of control subjects. Moreover, 100% of the alcoholics in both groups exhibited exceedingly low Vmax values that were below the 25th percentile of controls. In summary, results of MAO Vmax determinations provided us with a better separation of the alcoholics from controls. Measurements of platelet MAO function that include enzyme Vmax may provide us a reliable biochemical marker for alcoholism.

Adult↗

PubMed1993

Inactivation of monoamine oxidase B by analogues of the anticonvulsant agent milacemide (2-(n-pentylamino)acetamide).

Analogues of the anticonvulsant agent milacemide (1,2-(n-pentylamino)acetamide), in which the carboxamide group is changed to a nitrile (2), a carbethoxy group (3), a carboxylic acid (4), a cyanomethyl group (5), and a trifluoromethyl group (6), were synthesized and tested as substrates and inactivators of monoamine oxidase B (MAO B). The carboxylic acid was neither a substrate nor an inactivator. The trifluoromethyl compound was not soluble in buffer even when organic cosolvents were added, so it could not be tested. All of the other compounds were both substrates and time-dependent irreversible inactivators of MAO B. A plot of the logarithm of kcat/k(inact) (a measure of the efficiency of the inactivators) versus sigma I (Figure 1) shows a linear free energy relationship between the inactivator efficiency and the electron-withdrawing ability of the substituent. As the electron-withdrawing ability increases, the partition ratio decreases indicating that inactivation is becoming more efficient relative to substrate turnover to product. Milacemide was the least efficient of the compounds tested; the nitrile 2 was the most efficient.

Acetamides↗

PubMed1991

Quantitative localization of human brain monoamine oxidase B by large section autoradiography using L-[3H]deprenyl.

The distribution of monoamine oxidase B (MAO-B) in the human brain was studied by quantitative autoradiography using L-[3H]deprenyl as a ligand. Two postmortem brains from patients without any known neurological diseases were used in this study. Cryosections of 100 microns thickness were taken on tape/paper and transferred to gelatinized glass plates. The sections were incubated with 10 nM L-[3H]deprenyl for 1 h and exposed to a film at 4 degrees C for 4 weeks. The autoradiograms were analyzed by computerized densitometry. High L-[3H]deprenyl binding was observed in caudate nucleus, putamen, cingulate gyrus and insula cortex. Moderate to low binding was seen in globus pallidus, temporal and parietal cortex and in various thalamus nuclei. Occipital cortex showed the lowest binding among the cortex regions and white matter the lowest among all the regions studied. All the regions in case 2 (aged 67) showed higher degree of binding when compared with case 1 (aged 58), which is in agreement with previous results showing an increase in MAO-B activity with age. When the specific binding of L-[3H]deprenyl was plotted against the MAO-B activities estimated biochemically in punches from the same areas, a high positive correlation was found.

Adult↗

PubMed1985

Measurement of platelet monoamine oxidase using three different substrates in patients with alcoholism and schizophrenia.

The platelet monoamine oxidase (MAO) activities in alcoholism and schizophrenia were investigated by means of simultaneous determination, using beta-phenyl-ethylamine, tryptamine and serotonin as substrates. No significant difference was found between the MAO levels in the alcoholic and schizophrenic groups, when tryptamine was used as a substrate, but both groups showed lower values than the controls. On the other hand, beta-phenylethylamine, a specific substrate for MAO B used as a substrate, showed no significant difference between the alcoholic and control groups in the activities. These two groups showed higher values in MAO activity than the schizophrenic group, whereas when MAO activity was estimated using serotonin, platelet enzyme was found to be inhibited significantly in alcoholism, and the level of activities in the schizophrenics was similar to that of the controls. Moreover, the beta-phenylethylamine inhibition curve obtained serotonin as the substrate in the pooled platelets of 50 normal human subjects, and the MAO activity could not be inhibited by higher concentrations than the Km value of serotonin. These findings suggested that there might be two interacting catabolic sites having different substrate affinities in blood platelet MAO. Thus, it could be speculated that serotonergic catabolic sites of MAO in the platelets are disturbed in the alcoholics, while beta-phenylethylaminergic catabolic sites of platelet MAO are inherently vulnerable in schizophrenia.

Adult↗

PubMed2000

Localization of monoamine oxidase A and B in human pancreas, thyroid, and adrenal glands.

We studied monoamine oxidase (MAO) A and B localization in human pancreas, thyroid gland, and adrenal gland by immunohistochemistry. The primary antibodies used were mouse monoclonal anti-human MAO-A (6G11/E1) and anti-human MAO-B (3F12/G10/2E3). Samples were obtained from six routine autopsy cases and fixed in 2% paraformaldehyde. Exocrine pancreas showed a widespread distribution of MAO-A, whereas MAO-B was present only in centroacinar cells and epithelial cells of pancreatic ducts. In endocrine pancreas, MAO-A was observed in around 50% of islet cells, whereas MAO-B was less abundant and was restricted to the periphery of islets. Thyroid gland showed strong MAO-A immunoreactivity in all cell types and was MAO-B-negative. In adrenal gland, the capsule displayed MAO-A but not MAO-B immunoreactivity, whereas the cortex showed widespread MAO-A staining but was MAO-B-negative in interstitial cells. Finally, in the medulla only a few scattered cells showed either MAO-A or MAO-B immunoreactivity. To our knowledge, these data represent the first study of the cellular distribution of MAO-A and MAO-B in the three human tissues included.

Adrenal Glands↗

PubMed1995

Regions of the molecule responsible for substrate specificity of monoamine oxidase A and B: a chimeric enzyme analysis.

To examine regions of the monoamine oxidase (MAO, EC 1.4.3.4) molecule responsible for substrate recognition, a series of these enzymes, in which discrete regions in one molecule were substituted by corresponding sequences of the other, were constructed from the cDNAs of rat liver MAO A and MAO B and were expressed in yeast, Saccharomyces cerevisiae. Substrate specificities of the original and chimeric enzymes were examined in terms of the maximum activity (Vmax) and the affinity (Km) for serotonin, beta-phenylethylamine (PEA), and benzylamine. Chimeric enzymes with the amino-terminal portion (about 220 residues) and the amino-terminal and middle portions (about 400 residues) of MAO A and MAO B, respectively, exhibited substantially the same Km values as those of the parent enzymes. Extension of the substitution in the middle portion of a chimeric enzyme to the second half of the amino-terminal portion resulted in conversion of the Km values for serotonin to those of the counterpart. Data on relative Vmax values of the chimeric enzymes for the three substrates revealed that the relative catalytic activities were mainly determined by the presence of the middle portion. We conclude from these observations that the region between about residues 120-220 and about residues 50-400 is responsible for determination of the substrate specificity of MAO A and MAO B, respectively, while the middle portion, of about residues 220-400, may relate to the relative catalytic activity towards substrates.

Base Sequence↗

PubMed1995

Reversible and selective inhibitors of monoamine oxidase A in mental and other disorders.

The clinically tested reversible inhibitors of monoamine oxidase A (RIMAs) include brofaromine, moclobemide and toloxatone. Moclobemide has shown unequivocal antidepressant activity against serious depressive illness in 4 placebo-controlled double-blind trials. It has been compared with amitriptyline, imipramine, clomipramine, desipramine, maprotiline, fluoxetine, fluvoxamine, tranylcypromine, toloxatone, mianserin and amineptine in the treatment of depressive disorders. Meta-analysis showed convincing evidence of moclobemide efficacy, comparable with the most potent antidepressants available. The efficacy of moclobemide has been demonstrated in psychotic and non-psychotic depression, in depression with and without melancholia, in endogenous depression (both unipolar and bipolar), in retarded depression and in agitated depression. The efficacy of moclobemide, allied to the unusually benign side effect profile, has led to exploration of its use in other disorders. Two small studies have given encouraging results in the treatment of attention-deficit hyperactivity disorder. Large placebo-controlled studies have shown the activity of moclobemide in the depression that accompanies dementia (such as senile dementia of Alzheimer type). The results also suggested that, in this patient population, cognitive ability improved in parallel. Social phobia has also been shown to improve on treatment with either moclobemide or brofaromine. Clinical trials are in progress on the effect of moclobemide in chronic fatigue syndrome. Moreover, there are encouraging results with the use of brofaromine and moclobemide in panic disorder. Other disorders in which treatment with RIMA is of interest include agoraphobia, bulimia, borderline personality disorder, post-traumatic stress disorder, compulsive hair pulling (trichotillomania), dysmorphophobia, kleptomania as well as various anxiety syndromes.

Alzheimer Disease↗

PubMed1995

Aminium cation radical mechanism proposed for monoamine oxidase B catalysis: are there alternatives?

1. The interaction of bovine liver mitochondrial monoamine oxidase B (MAO B) with a series of benzylamine analogues was investigated to provide mechanistic information relative to the proposed cation radical mechanism and to provide information on the structural requirements of the substrate binding site. 2. Steady-state kinetic analysis of MAO B with 11 ring-substituted benzylamine analogues showed substitution does not alter the reaction pathway. All amine analogues tested exhibit sizeable deuterium kinetic isotope effects. 3. Anaerobic stopped-flow kinetic studies showed (1) C-H bond cleavage is rate-limiting in enzyme-bound flavin reduction and (2) that no specially detectable flavin radicals are observed. 4. The binding affinity of para-substituted benzylamine analogues to MAO B increased as the hydrophobicity of the substituent increased. In contrast, meta-substitution of the ring showed reduced affinity with an increase in the van der Waals volume of the substituent. 5. The rate of enzyme reduction by para-substitution exhibited a strong negative dependence with the Taft (Es) steric value of the substituent. In contrast, the rate of enzyme reduction by meta-substituted benzylamines is independent of the nature of the substituent. 6. para-Substituted N,N-dimethylbenzylamine analogues are not substrates for MAO B but are competitive inhibitors of benzylamine oxidation with a weaker affinity with increasing van der Waals volume of the substituent. In contrast, meta-substituted N,N-dimethyl benzylamine analogues are weak substrates for MAO B with oxidation occurring exclusively at the benzyl carbon. 7. The consequences of these results on the possible mechanisms (aminium cation radical, H abstraction, and nucleophilic mechanism) for C-H bond cleavage proposed for MAO B are discussed.

Amines↗

PubMed1981

Catecholamines and monoamine oxidase activity in anxiety.

Levels of platelet monamine oxidase activity, state anxiety and trait anxiety were quantified twice in 20 drug-free subjects with generalized anxiety and an equal number of healthy drug-free controls at 4-week intervals. Fifteen subjects in each groups also had plasma epinephrine and norepinephrine measured. The index group received relaxation training during the interval between the two evaluation sessions. Post-relaxation training values for monoamine oxidase, epinephrine, norepinephrine and the anxiety levels were found to be significantly lower than the pre-treatment values for the index group. No significant changes were seen in the control group values. For the index group, catecholamine levels and monoamine oxidase activity were seen to correlate significant before and after relaxation training.

Adult↗

PubMed2006

The lack of association between monoamine oxidase (MAO) intron 13 polymorphism and platelet MAO-B activity among men.

Monoamine oxidase (MAO), a mitochondrial flavine containing enzyme, exists in two isoenzymes, MAO-A and MAO-B. Platelets contain MAO-B subtype, proposed to be a biomarker for different personality characteristics and vulnerability for substance abuse. The most common polymorphism of MAO-B gene, a single base change (A or G) occurs in intron 13. It has been proposed to be a functional polymorphism, controlling the activity of MAO-B in platelets. The aim of the study was to determine the association between platelet MAO-B activity and MAO-B intron 13 polymorphism in 225 racially and ethnically uniform healthy Caucasian men of the Croatian origin. Our results showed that platelet MAO-B activity did not differ between subjects subdivided into those with < > or < >. This polymorphism of the MAO-B gene did not control the activity of the MAO-B in platelets. Platelet MAO-B activity was associated only with the smoking status, and it was significantly decreased in smokers when compared to nonsmokers. No significant association was found between MAO-B polymorphism and smoking status. In healthy individuals of the Croatian origin, the studied MAO-B polymorphism showed a lack of functional importance in regulating MAO-B activity in platelets. Since different populations may vary in the association between functional polymorphism and the MAO-B activity, and the genotype of transcription factor AP-2 beta was reported to be associated with altered platelet MAO-B activity, and with specific personality traits, further studies on different populations should be conducted to elucidate the molecular mechanism/s regulating platelet MAO-B activity.

Adult↗

PubMed1994

A new look at the promoter of the human monoamine oxidase A gene: mapping transcription initiation sites and capacity to drive luciferase expression.

Monoamine oxidase (MAO) A (EC 1.4.3.4) oxidizes norepinephrine and serotonin and is expressed in a cell type-specific manner. Recent evidence that MAO A-deficient males in a large Dutch kindred suffer from mild mental retardation and occasional episodes of impulsive aggressive behavior makes it important to understand how the human MAO A promoter is regulated. Conventional primer extension analyses of MAO A mRNA in earlier studies predicted incorrect transcription initiation sites for the human MAO A promoter. Reverse transcription and polymerase chain reaction (PCR) readily detected MAO A mRNA initiated 5' to -135 bp but not 5' to -226 bp (5' to the ATG initiation codon). PCR-assisted primer extension and RNase protection assays reveal that most MAO A mRNA is initiated between -30 and -40, which resembles a eukaryotic initiator element. Depending on the tissue source, a minor, variable proportion of MAO A mRNAs is initiated more distally at approximately -95 and -136, within the more proximal of two 90-bp GC-rich tandem repeats. Genomic DNA segments spanning -4 to -200 and -465 or -935, but not -4 to -82, drive robust luciferase expression in mammalian cells. We conclude that (a) the primary transcription initiation site occurs at a putative initiator (lnr) element located between -30 and -40, with a minor, tissue-specific proportion of additional initiation near -95 and -136; and (b) MAO A-luciferase reporter constructs that contained all the known transcription initiation sites exhibited no evidence for inhibitory cis elements between -200 and at least -935. The apparent inhibitory activity previously reported for sequences 5' to the most proximal PvuII site may have resulted from the use of partial promoter constructs that omitted the putative lnr element.

Base Sequence↗