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Platelet monoamine oxidase activity in elderly depressed outpatients.

Platelet monoamine oxidase (MAO) activity was assayed in 42 unmedicated, elderly, RDC depressed, unipolar outpatients over 60 years of age, 17 nondepressed controls, and 17 younger volunteers without psychiatric illness. Elderly depressed women (n = 22) had significantly higher MAO activity than sex- and age-comparable controls. No significant relationships between MAO activity and duration of current depressive episode, duration of illness, or family history of affective disorder were obtained. These results extend to elderly female outpatients the finding that depression is associated with increased platelet MAO activity, exceeding the normal age-related increase.

Aged↗

Isatin: identity with the purified endogenous monoamine oxidase inhibitor tribulin.

Purified tribulin, an endogenous monoamine oxidase (MAO) inhibitor, has been identified by direct probe insertion mass spectrometry as the indole-2,3-dione, isatin. A gas chromatographic-mass spectrometric assay for isatin has been developed and used to measure its relatively high concentrations in unpurified human urine, and in rat heart and brain. Isatin is a known compound with a broad range of biological activity; this is the first report of its presence in the animal body. Isatin is a potent inhibitor of MAO, particularly of MAO B (IC50, 3 microM), and also binds to central benzodiazepine receptors (IC50 against clonazepam, 123 microM).

Animals↗

Platelet monoamine oxidase: low activity in cigarette smokers.

Platelet monoamine oxidase (MAO) activity and plasma thiocyanate concentration (an index of smoking behavior) were measured in 109 normal male and female volunteers. MAO activity was significantly lower and plasma thiocyanate concentration significantly higher in smoking volunteers than in nonsmoking volunteers. A significant negative correlation between MAO activity and thiocyanate concentration was observed in female smokers (rs = 0.43, n = 36) but not for male smokers (rs = 0.02, n = 31). In nine smokers who gave up smoking, mean (+/- SD) platelet MAO activity increased significantly (17.5 +/- 4.1 nmole/mg/hour to 24.6 +/- 4.2 nmole/mg/hour). At the same time, mean (+/- SD) plasma thiocyanate concentrations decreased significantly (144 +/- 41 microM to 50 +/- 12 microM). These data suggest that smoking directly or indirectly reduced platelet MAO activity.

Adolescent↗

The behaviour of aryl pyrrolines with monoamine oxidase.

We have examined the effects of monoamine oxidase (MAO) on two pyrrolines, 1-methyl-3-phenyl-delta 3-pyrroline and its 4-chlorophenyl analogue. They act as substrates but also inhibit the enzyme in a time-dependent manner. This behaviour is similar to that shown by the neural pro-toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP) which is metabolised by MAO to produce the toxin 4-phenyl pyridinium (MPP+). The end product of the oxidation of the pyrrolines appears to be the corresponding pyrrole. The latter were found to inhibit MAO reversibly. The aryl pyrrolines bear close structural resemblance to MPTP and probably generate a pyrrolium ion, analogous to MPDP or MPP+, during the oxidation by MAO. Whether pyrrolines or their metabolites might mimic the effects of MPTP on mitochondrial respiration remains an unanswered question.

Animals↗

Anorexic properties of three monoamine oxidase inhibitors.

The anorexic properties of 3 monoamine oxidase (MAO) inhibitors, pargyline, tranylcypromine and nialamide were determined 24 hr after their intra-peritoneal administration. The duration of anorexia occurring after the peripheral administration of the dose of pargyline commonly used in conjunction with 6-hydroxydopamine (6-OHDA) to enhance its dopamine-depleting properties was also determined. Body weight regulation and the control of food and water intake were severely impaired 24 hr after the administration of the three highest doses of pargyline, tranylcypromine and nialamide employed. Impairment in the ability to regulate body weight lasted for as long as 6 days in some animals injected with 50 mg/kg of pargyline. These findings bring to light the problems in interpretation of results from studies which employ MAO inhibitors and 6-OHDA simultaneously to enhance dopamine depleting properties of 6-OHDA.

Animals↗

The in vitro insertion of monoamine oxidase B into mitochondrial outer membranes.

Bovine monoamine oxidase (MAO) B has been synthesized in vitro using a reticulocyte lysate translation system directed by bovine liver poly(A)+ RNA. The newly synthesized enzyme apparently lacks a cleavable N-terminal extension, but MAO B is readily incorporated into mitochondria or isolated mitochondrial outer membranes prepared from rat liver. ATP is not required for the binding of the newly synthesized enzyme to the outer membranes, but is necessary for the insertion of MAO B into these membrane vesicles. The ATP is not required to generate a mitochondrial membrane potential as assembly occurs under conditions that preclude either the formation or the maintenance of the potential. MAO B will bind to but not become incorporated into outer membrane vesicles which have been treated with trypsin, suggesting that the insertion of MAO B also depends on protein factors present on the outer membranes.

Animals↗

No evidence of an association between a functional monoamine oxidase a gene polymorphism and completed suicides.

Monoamine oxidase A (MAOA) has been implicated in the control of aggression and/or impulsivity in humans and been involved in suicide. This gene has a functional polymorphism in which there is a variable number tandem repeat (VNTR) in the upstream region (MAOA-uVNTR). We hypothesized that MAOA dysfunction due to this polymorphism was associated with suicide genetically through the disinhibition of aggression and/or impulsivity. We performed an association study between completed suicides and the MAOA-uVNTR polymorphism. No significant difference in genotype distribution or allele frequencies was found between completed suicides and comparison groups either in males or females. These results show no evidence of an association between the MAOA-uVNTR polymorphism and completed suicides and suggest that MAOA is not involved in the susceptibility to suicide.

Adult↗

Low platelet monoamine oxidase activity in pathological gambling.

Decreased platelet monoamine oxidase (MAO) activity has been reported in association with sensation-seeking personality type and in some mental disorders associated with a lack of impulse control. Pathological gambling itself has been related with both sensation-seeking and reduced impulse control. Platelet MAO activity was investigated in 15 DSM-III-R pathological gamblers from our outpatient clinic. Gamblers had a significantly lower platelet MAO activity than a group of 25 healthy controls. The range of MAO levels in gamblers was also significantly shorter than in controls. In controls, platelet MAO levels showed the previously described negative correlations with sensation-seeking scores but not in gamblers. The findings are consistent with previous studies showing an association of low platelet MAO activity with impulse control disorders and raise some interesting therapeutic alternatives for pathological gambling.

Adult↗

Interference by endogenous amines in the determination of monoamine oxidase activity of human platelet samples.

Lower monoamine oxidase (MAO) levels are reported in the blood platelets from chronic schizophrenics than in normal controls. Attempts to replicate these findings in other laboratories have been unsuccessful thus contradicting the suggestion that low MAO activity is a genetically determined biological factor in schizophrenia. We now present evidence to show that the endogenous amines present in platelets (serotonin) react non-enzymatically with the highly reactive aldehyde produced by MAO and thereby reduce the extractable radioactivity in the radiometric assays for MAO. Various biogenic amines such as serotonin, dopamine and m-tyramine were tested for their interference by adding them in nanomolar concentrations to incubation mixtures containing platelet samples or partially purified rat liver MAO and (14C-)p-tyramine or phenethylamine as substrates. The amines were added before, during and after incubation. In all three cases the apparent inhibition by each amine was the same, the percent inhibition depending on the structure of the amine.

Acetaldehyde↗

Platelet monoamine oxidase activity in female migraine patients.

Platelet monoamine oxidase activity (MAO) in a group (n = 17) of white, female migraineurs during an acute migraine attack was similar to both the values obtained for the same group of patients two to three weeks after the headache episode (pain-free period) and to the results obtained for a group (n = 18) of sex and race-matched, age-comparable, drug-free healthy volunteers (blind study; substrate p-tyramine, 38.7 +/- 5.7, 41.9 +/- 8.8 and 43.0 +/- 3.4 or p-methoxybenzylamine, 178.9 +/- 11.3, 177.2 +/- 6.9 and 181.0 +/- 9.7 nmole/hr/10(9) platelets +/- SD respectively). With each patient serving as its own control, MAO activity during the migraine episode and when pain-free failed to show a significant trend. Neither a number of other medical conditions nor the use of several medications appeared to significantly influence our results. The present work, while dealing only with a small but well defined patient population, argues against the possible usefulness of platelet MAO activity as a biological marker for migraine headaches.

Adult↗

Kinetics and metabolism of p-tyramine during monoamine oxidase inhibition by mofegiline.

The effects of monoamine oxidase B (MAO-B) inhibition by mofegiline on the pharmacokinetics of p-tyramine and its major metabolite, p-hydroxyphenylacetic acid, were investigated in 24 healthy male volunteers. p-Tyramine doses were administered before and after a 14-day treatment period of 1, 12, or 24 mg mofegiline or placebo. Normalized p-tyramine for area under the plasma concentration-time curve after treatment were not significantly different from their respective before-treatment values for any of the dose groups. The relative bioavailability of p-tyramine after treatment was not significantly different from before treatment, although a tendency to a greater bioavailability was seen with the 12 and 24 mg doses. There were no significant differences between pharmacokinetic parameters for p-hydroxyphenylacetic acid. The data suggest that mofegiline maintains its selectivity for MAO-B in the intestine and liver at doses up to and including 24 mg. Therefore these doses would not be expected to be associated with the hypertensive crises normally associated with the "cheese effect."

Adult↗

A regulatory monoamine oxidase a promoter polymorphism and personality traits.

Monoamine oxidase type A (MAOA) has been implicated to be part of mechanisms underlying human temperament and psychiatric disorders. We hypothesised that a functional polymorphism in the 5' untranslated region of the MAOA gene is associated with specific personality traits. In 371 healthy Caucasians, we estimated personality traits by the use of the Karolinska Scales of Personality (KSP), Scandinavian Universities Scales of Personality, Health-Relevant 5-Factor Personality inventory, Temperament and Character Inventory and the revised NEO Personality Inventory. In the same subjects, we analysed the genotype of a polymorphic region consisting of a variable number of a 30-bp repeat sequence located approximately 1.2 kb upstream of the MAOA gene. After correction for multiple testing, no statistically significant differences between MAOA genotype and personality were observed in men (n = 206) nor in women (n = 165). We conclude that the structure of this MAOA promoter region does not have a large impact on the expression of personality characteristics in the present Swedish population.

Adult↗

Purification and immunochemical characterization of monoamine oxidase from rat and human liver.

1. Monoamine oxidase from rat and human liver was purified to homogeneity by the criterion of polyacrylamide-gel electrophoresis in the presence of sodium dodecyl sulphate. 2. The enzyme activity was extracted from mitochondrial preparations by Triton X-100. The enzyme was purified by (NH4)2SO4 fractionation followed by chromatography on DEAE-cellulose, Sepharose 6B, spheroidal hydroxyapatite, and finally chromatography on diazo-coupled tyramine-Sepharose. 3. Distinct differences occur in the chromatographic behaviour of the two enzymes on both DEAE-cellulose and spheroidal hydroxyapatite. 4. It is unlikely that the purification of the enzymes on tyramine-Sepharose is due to affinity chromatography and reasons for this are discussed. 5. The purified enzymes did not oxidize-5-hydroxytryptamine and the relative activities of the enzymes with benzylamine were increased approx. 1.25-fold compared with the enzyme activities of mitochondrial preparations. 6. Immunotitration of enzyme activity in extracts of mitochondrial preparations from rat liver was carried out with 5-hydroxytryptamine, tyramine and benzylamine. The enzyme activities were completely immunoprecipitated by the same volume of antiserum. Similar results were obtained with the antiserum to the enzyme from human liver.

Animals↗

Kinetics and thermolability of platelet monoamine oxidase in cluster headache and migraine.

Platelet monoamine oxidase activity (MAO) from 33 cluster headache patients (17 males, 16 females) and 34 migraine patients (16 males, 18 females) was assayed. The kinetic constants (apparent Vmax and apparent Km) and the thermolability, measured as the ratio of the platelet MAO activity after and before heat treatment (+52 degrees C, 30 min), were determined. The MAO activity and Vmax values were significantly lower in cluster headache than in migraine and in both headache disorders compared to a control group (62 males, 66 females). When comparing all groups, Km was not significantly different except for migraine females, who had lower Km values compared to control females. Thermolability was significantly higher in cluster headache than in migraine and in both headache disorders compared to the control group. Smokers of five cigarettes or more per day had significantly lower Vmax values but similar Km and thermolability values compared to those smoking less or nothing. The findings of low maximal velocities and high thermolability of platelet MAO in cluster headache and migraine are suggested to represent constitutionally different enzyme properties.

Adolescent↗

Blood platelet monoamine oxidase activity in anergic schizophrenics.

Blood platelet monoamine oxidase (MAO) activity was evaluated in twenty-four anergic, schizophrenic outpatients during a double-blind study comparing a chlorpromazine-imipramine combination to thio-thixeneplacebo. Platelet MAO activity was determined on blood samples drawn after a two-week drug-free washout and once weekly over a four-week on-drug period. Schizophrenic patients could be classified according to their blood platelet MAO activity into either a low-MAO or a high-MAO group. In neither group of this population of schizophrenics did blood platelet MAO activity correlate with any of the primary or secondary symptoms of schizophrenia. Ten alcoholics and seven volunteer non-patients could similarly be divided into low- and high-MAO groups. Mean blood platelet MAO activity for these groups was not significantly different from the mean values of the low and high-MAO groups of the schizophrenics. These findings do not support published reports of low blood platelet activity as a genetic marker for schizophrenia. Discriminate function analysis of symptomatology ratings at baseline was used to characterize the low- and high-MAO schizophrenic patient groups. Individuals in the low-MAO group were distinguished by hyperactivity, anergia and sleep disturbance.

Alcoholism↗

Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver.

Citalopram (CIT) is an antidepressive drug of the group of selective serotonin reuptake inhibitors (SSRIs). The tertiary amine CIT is given as a racemic drug, but its pharmacological activity resides mainly in S-CIT. CIT is metabolised by cytochrome P450 (CYP) to N-demethylcitalopram (DCIT) and N-didemethylcitalopram (DDCIT). The citalopram propionic acid derivative (CIT-PROP) is another, but pharmacologically inactive, metabolite, the formation of which has been poorly characterised but is postulated to occur by deamination of CIT, DCIT and/or DDCIT. The aim of the present investigation was to study the formation of the enantiomers of CIT-PROP from CIT and its two N-demethylated metabolites, DCIT and DDCIT, in an in vitro incubation system (microsomal and cytosolic fractions) obtained from human livers. The production of CIT-PROP was measured by a stereospecific HPLC method. Incubation of rac-CIT, rac-DCIT and rac-DDCIT (500 microM each, separately) in the presence (or absence) of NADP showed that CIT-PROP formation was substrate-dependent and essentially NADP-independent. Monoamine oxidases (MAO) type A and B and aldehyde oxidase were identified as the probable enzymes involved in the formation of CIT-PROP from CIT, DCIT and DDCIT. Indeed, the irreversible monoamine oxidase type A inhibitor clorgyline and the irreversible monoamine oxidase type B inhibitor selegiline (both at 0.5 microM in the incubation mixture) inhibited CIT-PROP formation, depending on the substrate, up to 70% and 88%, respectively. The participation of aldehyde oxidase in the subsequent step is suggested by the inhibition caused by menadione (50 microM) in CIT-PROP formation. Preliminary experiments suggest the presence of four unknown metabolites, probably products of deamination, which were detected in plasma and urine samples of patients treated with CIT as well as in in vitro biotransformations. Their presence confirms the importance of deamination in the biotransformation of CIT and its demethylated metabolites, especially in the brain where, in contrast to the liver, the role of cytochrome P450 appears to be low.

Adult↗

Cluster B personality disorders are associated with allelic variation of monoamine oxidase A activity.

Genetic variants of the monoamine oxidase A (MAOA) have been associated with aggression-, anxiety-, and addiction-related behavior in several nonclinical and clinical populations. Here, we investigated the influence of allelic variation of MAOA activity on aggression-related personality traits and disease risk in patients with personality disorders. Personality disorders were diagnosed with the Structured Clinical Interview of DSM-IV and were allocated to cluster A, B, and C. Personality features were assessed by the revised NEO Personality Inventory and the Tridimensional Personality Questionnaire. The genotype of the MAOA gene-linked polymorphic region (MAOA-LPR) was determined in 566 patients with personality disorders and in 281 healthy controls. MAOA genotype was significantly associated with cluster B personality disorders (chi2=7.77, p=0.005, df=1) but not with cluster C personality disorders. In total, 26.0% of cluster B patients were hemi- or homozygous for the low-activity variant of the MAOA genotype, compared to 16.4% in the control group. Associations between MAOA variants and personality domains related to impulsivity and aggressiveness were inconsistent. Our findings further support the notion that allelic variation of MAOA activity contributes modestly to the balance of hyper- (impulsive-aggressive) and hyporeactive (anxious-depressive) traits.

Adolescent↗

Toward a biochemical classification of depressive disorders--VIII. Platelet monoamine oxidase activity in subtypes of depressions.

Platelet monoamine oxidase (MAO) activity was examined in 77 depressed patients (40 males and 37 females) and 28 controls (14 males and 14 females). Patients were compared across increasingly specific diagnostic groupings in a four-step data analytic procedure. In step 1, MAO activity in the total sample of depressed patients was compared with that of control subjects. In step 2, Unipolar depressed patients were compared with Bipolar (Bipolar I and Bipolar II) depressed patients. In step 3, Unipolar depressed patients with and without schizotypal features were compared. In step 4, both the nonschizotypal Unipolar patients and compared. In step 4, both the nonschizotypal Unipolar patients and nonschizotypal Bipolar patients were separated into those who met RDC criteria for a definite Endogenous depression and those who did not; and platelet MAO activity was compared in the resulting four groups. Results indicated significantly higher platelet MAO activity in nonschizotypal Unipolar Endogenous depressed patients than in nonschizotypal Bipolar Endogenous depressed patients or nonschizotypal Unipolar Other patients. In addition, the presence of a definite Endogenous depressive syndrome was associated with greater overall symptom severity in both Unipolar and Bipolar depressed patients. Findings are discussed with respect to the conflicting results reported in previous studies of MAO activity in patients with depressive disorders.

Adolescent↗