Showing papers on "Monoamine oxidase B published in 1988"
TL;DR: Both monoamine oxidase A and B were localized in distinct populations of neurons in the lateral and tuberal regions of the hypothalamus, a region shown recently to contain histamine neurons in rats.
352 citations
TL;DR: Purified tribulin, an endogenous monoamine oxidase (MAO) inhibitor, has been identified by direct probe insertion mass spectrometry as the indole‐2,3‐dione, isatin, the first report of its presence in the animal body.
Abstract: 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).
200 citations
TL;DR: Coexistent PD pathology can explain the loss of DA in the striatum and the presence of clinical PD symptoms in some patients with AD/SDAT, but the clinical relevance of these dopaminergic alterations is unclear.
114 citations
Journal Article•
TL;DR: The major effect of tianeptine in rat platelets and synaptosomes is a small increase in 5-HT uptake after subchronic administration.
Abstract: Tianeptine is a new effective antidepressant drug. However, its neurochemical profile in animals differs from that of tricyclic or atypical antidepressants. In the present study, we compared the ex vivo effects of tianeptine on platelet serotonin uptake to those of clomipramine. Ex vivo, after subchronic (15 days, washout 24 h) treatment (10 mg/kg/day i.p.) in rats, tianeptine induced an increase (30%) in [14C]serotonin uptake at a [14C]serotonin concentration of 500 nM while clomipramine induced a decrease (40%) in [14C]serotonin uptake. Stimulation of uptake affected mainly Vmax but not Km. Tianeptine did not inhibit monoamine oxidase (MAO), MAOA or MAOB activity. In vitro, there was no binding of tianeptine to any of the various receptors examined: alpha- and beta-adrenergic, dopamine, serotonin, imipramine, GABA, glutamate, benzodiazepine, muscarinic, histamine, Ca2+ channels. After chronic administration (10 mg/kg/day for 15 days) tianeptine did not alter the concentration (Bmax) or the affinity (Kd) of alpha-2, beta-1, serotonin-1, serotonin-2, imipramine, benzodiazepine, or GABAB receptors. The major effect of tianeptine in rat platelets and synaptosomes is a small increase in 5-HT uptake after subchronic administration.
105 citations
TL;DR: In most of the brain areas examined, except the serotonergic dorsal nucleus of raphe, the noradrenergic locus coeruleus and the dorsal efferent nucleus of vagus, tyrosine hydroxylase-positive neurons were in greater number than monoamine oxidase-A-stained or monoamine oxidation-B-stained neurons.
102 citations
TL;DR: The low level of monoamine oxidase B in the nigrostriatal tract may help to explain the resistance of the rat to MPTP toxicity and appear to have a different role in these three types of neuron.
Abstract: The histochemical distribution of monoamine oxidase A and B in rat brain was investigated using a coupled peroxidatic technique with benzylamine and tyramine as substrates and clorgyline and (−)-deprenyl as selective inhibitors. Benzylamine oxidase was absent in all areas. Both forms of monoamine oxidase were present, at low levels, in all areas; in addition several regions showed high activity of one or other form or both. Substantial activity of monoamine oxidase B was identified in the pineal gland, the lining of the ventricles, several hypothalamic regions, and the raphe nuclei. The locus coeruleus and interpeduncular nucleus possessed considerable type A activity. The substantia nigra and striatum showed no staining above the low general level, although the ventral tegmental area showed higher levels of both A and B.
92 citations
TL;DR: It is proposed that calcium ions are of major importance in the mechanism of MPTP- and MPP+-induced toxicity in hepatocytes because they are associated with the impairment of the cell's Ca2+ extrusion system.
88 citations
TL;DR: The present data demonstrate that milacemide is a substrate for brain MAO‐B, and its conversion to glycinamide, further transformed to the inhibitory neurotransmitter, glycine, mediated by this enzyme may contribute to its pharmacological activities.
Abstract: Milacemide (2-n-pentylaminoacetamide) is a secondary monoamine that in the brain is converted to glycinamide and glycine. This oxidative reaction was suspected to involve the reaction of monoamine oxidase (MAO). Using mitochondrial preparations from tissues that contain MAO-A and -B (rat brain and liver), MAO-A (human placenta), and MAO-B (human platelet and bovine adrenal chromaffin cell), it has been established that mitochondria containing MAO-B rather than MAO-A oxidize (H2O2 production and glycinamide formation) milacemide. The apparent Km (30-90 microM) for milacemide oxidation by mitochondrial MAO-B preparations is significantly lower than that for milacemide oxidation by mitochondrial MAO-A (approximately 1,300 microM). In vitro MAO-B (l-deprenyl and AGN 1135) rather than MAO-A (clorgyline) selectively inhibited the oxidation of milacemide. These in vitro data are matched by ex vivo experiments where milacemide oxidation was compared to oxidation of serotonin (MAO-A) and beta-phenylethylamine (MAO-B) by brain mitochondria prepared from rats pretreated with clorgyline (0.5-10 mg/kg) and l-deprenyl (0.5-10 mg/kg). Furthermore, in vivo experiment demonstrated that l-deprenyl selectively increased the urinary excretion of [14C]milacemide and the total radioactivity with a concomitant decrease of [14C]glycinamide. Such changes were not observed after clorgyline treatment, but were evident only at doses beyond clorgyline selectivity. The present data therefore demonstrate that milacemide is a substrate for brain MAO-B, and its conversion to glycinamide, further transformed to the inhibitory neurotransmitter, glycine, mediated by this enzyme may contribute to its pharmacological activities.
80 citations
TL;DR: The cDNA for rat monoamine oxidase B mRNA was isolated from liver cDNA library in lambda gt11 using specific antibody and oligonucleotide probes derived from FAD-containing peptide of the enzyme in good agreement with that of the in vitro-synthesized peptide.
70 citations
TL;DR: Two hours of cold restraint stress in rats resulted in significantly increased brain concentrations of endogenous monoamine oxidase inhibitor (tribulin) and Tribulin levels were also increased by immobilisation stress alone but to a lesser extent.
67 citations
TL;DR: The two molecular forms of monoamine oxidase (MAO), MAO-A andMAO-B, were determined quantitatively in discrete regions of the human brain at autopsy, and in cerebral microvessels, choroid plexus and liver samples from the same subjects.
Abstract: The two molecular forms of monoamine oxidase (MAO), MAO-A and MAO-B, were determined quantitatively in discrete regions of the human brain at autopsy, and in cerebral microvessels, choroid plexus and liver samples from the same subjects. MAO was assessed by specific[3H] pargyline binding, which is stoichiometric and irreversible, and by measuring the rate of oxidation of several MAO substrates. Basal ganglia structures (caudate, putamen, globus pallidus and substantia nigra) and hippocampus had about twice the levels of MAO that were present in the cerebral cortex and cerebellum. Cerebral microvessels, which constitute the blood-brain barrier, had minimal MAO, while the choroid plexus, which constitutes the blood-cerebrospinal fluid barrier, and the liver had higher MAO levels than any brain region. The vast majority of MAO (80-95%) in these tissues was of the B type, except in microvessels, where total MAO activity was low. Specific [3H]pargyline binding correlated well with the oxidation rates for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and benzylamine in all tissues. Both specific [3H]pargyline binding and the rate of oxidation of MAO substrates increased with age.
TL;DR: The data support the conclusion that both 2'-MeMPTP and 2'-EtMPTP are bioactivated to pyridinium species to a significant extent by MAO-A, and it appears that the formation of the pyridine species plays an important role in the neurotoxic process.
Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent dopaminergic neurotoxin that causes biochemical, pharmacological, and pathological deficits in experimental animals similar to those seen in human parkinsonian patients. All of the deficits can be prevented by treating mice with selective inhibitors of monoamine oxidase B (MAO-B), including deprenyl, prior to MPTP administration. We now report that the dopaminergic neurotoxicity of two potent MPTP analogs, namely the 2'-methyl and 2'-ethyl derivatives (2'-MeMPTP and 2'-EtMPTP), cannot be prevented by deprenyl pretreatment. However, the neurotoxicity of these two analogs can be prevented by pretreatment with a combination of deprenyl and the selective MAO-A inhibitor clorgyline at doses that are sufficient to almost completely inhibit both MAO-B and MAO-A activities. Moreover, the neurotoxicity of 2'-EtMPTP (but not of 2'-MeMPTP and MPTP) can be significantly attenuated by clorgyline alone. There was a parallel between the capacity of the MAO inhibitors to decrease the brain content of the pyridinium species after administration of the tetrahydropyridines and the capacity of the MAO inhibitors to protect against the neurotoxic action of the tetrahydropyridines. The data support the conclusion that both 2'-MeMPTP and 2'-EtMPTP are bioactivated to pyridinium species to a significant extent by MAO-A. Further, it appears that the formation of the pyridinium species plays an important role in the neurotoxic process.
Journal Article•
TL;DR: Studies with everted intestines showed that at concentrations above 10 microM over 70% of tyramine was deaminated during transport and the use of selective inhibitors confirmed the A-form of monoamine oxidase to play the dominant role in that process.
Abstract: The monoamine oxidase activities were found to be similar in the crypt and villous cells of the different regions of rat small intestine. In all cases the activity of the A-form of the enzyme constituted more than 70% of the total. A similar proportion of that form of the enzyme was found in homogenates of biopsy samples of human intestine. Studies with everted intestines showed that at concentrations above 10 microM over 70% of tyramine was deaminated during transport and the use of selective inhibitors confirmed the A-form of monoamine oxidase to play the dominant role in that process.
TL;DR: The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAo-B.
Abstract: The human platelet in addition to having serotonin (5-HT) receptors, uptake carriers (receptor) and transmitter storage vesicles, primarily possesses mitochondrial monoamine oxidase (MAO) type B. Similar to the major form of MAO in the human brain, this enzyme actively oxidizes A-B and B substrates (tyramine, dopamine, phenylethylamine) as well as the novel secondary amine anticonvulsant, milacemide and dopaminergic neurotoxin, MPTP. 5-HT oxidation is hardly affected by the platelet enzyme and MAO inhibitors have no net effect on its accumulation. MAO-B is selectively inhibited by 1-deprenyl and thus the platelet enzyme may be useful to monitor the anti-Parkinson activity of such drugs, as related to their ability to inhibit brain MAO-B. The oxidation of the anticonvulsant, milacemide, to glycine in vitro and in vivo by MAO-B, may herald new prospects for the development of inert prodrugs capable of being metabolized to neuroactive substances by MAO-B. The plasma levels of their metabolites may be an index of MAO-B activity found in the platelet and brain.
TL;DR: It is suggested that chronic nonselective and chronic MAO A inhibition causes a down-regulation of the 5-HT1A-mediated inhibition of forskolin-stimulated adenylate cyclase activity.
TL;DR: The histochemical localisation of monoamine oxidase (MAO) in marmoset brain was described, and high activity was present in the raphe nuclei, however, unlike the rat, no enrichment of MAO B was observed in blood vessels or ventricular linings.
TL;DR: Structural-activity relationships suggest that these oxadiazinones should interact with a hydrophobic site and a nucleophilic site on MAO B for binding, while the functional group of the N-4 substituent should compete with the substrate for the active site of the enzyme.
TL;DR: There is a greatly reduced propensity to potentiate the cardiovascular effects of tyramine under these conditions, under which therapy has potential in the treatment of affective disorders.
Abstract: 1. Selective inhibitors of the monoamine oxidase (MAO) isoenzymes, types A and B, are of potential therapeutic utility. Brain selectivity would overcome the risk of tyramine interactions which have been shown to occur with selective MAO-A but not MAO-B inhibitors. 2. (E)-3-Fluoroallylamines of general structure, FHC = C(R)CH2NH2 have been designed as enzyme-activated, irreversible inhibitors of these enzymes. Two compounds, MDL 72145 (R = 3,4 dimethoxyphenyl) and MDL 72974 (R = 4-fluorophenethyl), are selective and irreversible inhibitors of MAO type B which in vivo show high inhibitory potency against the rat brain enzyme (ED50 0.35 and 0.18 mg/kg p.o., respectively). In animals, these inhibitors do not potentiate the cardiovascular effects of tyramine and have no amphetamine-like effects. However, they do potentiate the central effects of L-Dopa and prevent the neurotoxic effects of MPTP in both mice and monkeys. 3. In early clinical studies, MDL 72145 has been shown to be a potent, long-acting inhibitor of MAO type B. Doses of 16 mg per patient totally inhibit platelet enzyme without potentiating the cardiovascular effects of oral tyramine. Compounds of this type should prove useful in Parkinson's disease. 4. Selective inhibition of brain MAO-A can be achieved by using the bioprecursor amino acid MDL 72394 (E-beta-fluoromethylene-m-tyrosine). This amino acid is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392 (R = 3-hydroxyphenyl), a potent irreversible inhibitor of MAO-A. Combination of MDL 72394 with a peripherally selective inhibitor of AADC (e.g., carbidopa) restricts MAO inhibition to the brain. Consequently, under these conditions, there is a greatly reduced propensity to potentiate the cardiovascular effects of tyramine. 5. This has been confirmed in human volunteers; MDL 72394 (8 mg), combined with carbidopa, substantially decreased urinary MHPG and plasma DHPG concentrations with minimal potentiation of the cardiovascular effects of i.v. tyramine. These results predict that such therapy has potential in the treatment of affective disorders.
TL;DR: It is demonstrated that, in cultures, MPTP is oxidized predominantly by monoamine oxidase B, since deprenyl but not clorgyline had an inhibitory effect on its metabolism.
Abstract: The metabolism of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was studied in dissociated cell cultures prepared from embryonic rat mesencephalon. MPTP was added to the feeding medium and at the end of the incubation period MPTP was separated from the water-soluble metabolite by ether extraction. Our results demonstrate that, in cultures, MPTP is oxidized predominantly by monoamine oxidase B, since deprenyl but not clorgyline had an inhibitory effect on its metabolism. The metabolite of MPTP diffuses freely in the feeding medium (99% of the total) and its concentration increases with time. The concentration of the metabolite can be increased by increasing the number of cells plated into the tissue culture dish and the toxicity to dopamine neurons depends on the amount of metabolite accumulated in the feeding medium. The metabolism of MPTP is reduced by decreasing the number of glial cells present in the cultures.
TL;DR: It appears that mitochondrial and microsomal MAO are related enzymes, although further structural studies are necessary to confirm their possible identity.
TL;DR: The discovery of two MPTP analogs with enhanced selective neurotoxicity to dopaminergic neurons may be an important clue in the continuing efforts to define the chemical structure‐activity factors governing MPTP neurotoxic activation mechanisms.
Abstract: We synthesized a number of fluorinated analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and tested their suitability as substrates for monoamine oxidase B in vitro and their dopaminergic neurotoxicity in vivo. Two of the compounds tested, 2′-F-MPTP and 2′-CF3-MPTP, were better enzyme substrates and possessed more potent neurotoxicity for nigrostriatal dopamine neurons than MPTP, especially 2′-F-MPTP. The results of the in vivo neurotoxicity experiments correlated well with the suitability of the compounds as substrates for monoamine oxidase. These findings could serve as a basis for the use of 18F-labeled analogs of MPTP for positron emission tomography studies of nonhuman primates for better understanding of the factors underlying MPTP toxicity. Furthermore, the discovery of two MPTP analogs with enhanced selective neurotoxicity to dopaminergic neurons may be an important clue in the continuing efforts to define the chemical structure-activity factors governing MPTP neurotoxic activation mechanisms.
TL;DR: The novel glycine-prodrug anticonvulsant milacemide significantly increased (greater than 400% the seizure threshold induced by hyperbaric oxygen) and that this reaction is mediated primarily by monoamine oxidase B is suggested.
TL;DR: The observations show a new aspect of the MPP+ mode of action, in which deprenyl in mice has a partially protective effect against MPP+.
Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) destroys nigrostriatal dopaminergic pathways and thereby produces a syndrome similar to Parkinson's disease. MPTP is oxidized by monoamine oxidase B (MAO B) to the 1-methyl-4-phenylpyridinium ion (MPP+), which is taken up in dopaminergic neurons through the dopamine (DA) uptake system, where it develops its toxic effect. Our observations show a new aspect of the MPP+ mode of action, in which deprenyl in mice has a partially protective effect against MPP+. Furthermore budipine, a therapeutic agent for Parkinsonism, is also able to partially prevent MPP+ toxicity. A MAO B-inhibitory component of budipine, as shown in receptor binding studies previously, could contribute to this effect. Comparable experiments with nomifensine do not exclude the possibility of budipine as an effect as a DA uptake inhibitor. An unexplained after effect of budipine leads to a large increase in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels five weeks after the last administration.
TL;DR: Results indicate that 5,6‐dihydroxytryptamine acts to displace serotonin from vesicular stores into the cytoplasm where it can either be deaminated by monoamine oxidase or be released.
Abstract: 5,6-Dihydroxytryptamine is a neurotoxic analogue of serotonin which can have profound cardiovascular effects within minutes of administration in vivo (Korner and Head, 1981). These effects have been attributed to 5,6-dihydroxytryptamine-induced serotonin release, although there has been no biochemical assessment of the extent to which this occurs. The present study utilized an in vitro synaptosomal assay to determine the short-term effects of 5,6-dihydroxytryptamine on endogenous serotonin release, synthesis, storage, and metabolism. 5,6-Dihydroxytryptamine produced a rapid depletion of serotonin. At lower concentrations of 5,6-dihydroxytryptamine (0.1-1 microM), this depletion was associated primarily with an increase in the levels of 5-hydroxyindoleacetic acid, the deaminated metabolite of serotonin, with small increases in the amount of serotonin release. At higher concentrations (10-100 microM), a greater proportion of the depleted serotonin was released with less metabolism occurring. When metabolism was prevented by inhibiting monoamine oxidase, the amount of serotonin which was released equalled the amount of serotonin depletion. Thus monoamine oxidase activity was important in controlling the amount of serotonin which could be released by 5,6-dihydroxytryptamine. Further studies demonstrated that an impairment in serotonin synthesis and vesicular storage could account for the rapid depletion produced by 5,6-dihydroxytryptamine. Taken together, the results indicate that 5,6-dihydroxytryptamine acts to displace serotonin from vesicular stores into the cytoplasm where it can either be deaminated by monoamine oxidase or be released. Moreover, it is hypothesized that the intraneuronal concentration of 5,6-dihydroxytryptamine is important in determining the extent of serotonin release, because it can inhibit the deamination of serotonin by monoamine oxidase.
TL;DR: It is suggested that patients treated with selegiline 30 mg/day or more should be placed on a tyramine-free diet.
Abstract: Blood pressure and heart rate responses to oral tyramine have been measured in healthy volunteers before and after administration of the selective monoamine oxidase B inhibitor selegiline at high dosage (30 mg/day). Treatment brought about a 2 to 4-fold increase in tyramine sensitivity and a concomitant small but significant reduction in plasma 4-hydroxy-3-methoxyphenylglycol concentration, pointing to the emergence of some degree of monoamine oxidase A inhibition. It is suggested that patients treated with selegiline 30 mg/day or more should be placed on a tyramine-free diet.
TL;DR: The ability of N-C alpha MBA to undergo attachment to a cysteine residue in both MAO A and MAO B may lead the way toward peptide mapping of the two isozymes in order to determine differences in their primary structures.
Abstract: Three known mechanism-based inactivators of beef liver mitochondrial monoamine oxidase (MAO) B are tested as inactivators of human placental mitochondrial MAO A. 1-Phenylcyclopropylamine (1-PCPA), 1-benzylcyclopropylamine (1-BCPA), and N-cyclopropyl-alpha-methylbenzylamine (N-C alpha MBA) are time-dependent irreversible inactivators of MAO A. The KI values for 1-PCPA and N-C alpha MBA, analogues of the MAO B substrate benzylamine, are much higher with MAO A than with MAO B. Evidence is presented to show that 1-PCPA inactivates MAO A by attachment to the flavin cofactor, unlike the reaction with MAO B in which 1-PCPA can attach to both a cysteine residue and the flavin [Silverman, R.B., & Zieske, P.A. (1985) Biochemistry 24, 2128-2138]. The reaction of 1-BCPA with MAO A was too slow to study in detail. N-C alpha MBA exhibits the same properties toward inactivation of MAO A that it does for inactivation of MAO B. Attachment in both cases is shown to be to one cysteine residue per enzyme molecule. The results with 1-PCPA indicate that the active site topographies of MAO A and MAO B are different. The ability of N-C alpha MBA to undergo attachment to a cysteine residue in both MAO A and MAO B may lead the way toward peptide mapping of the two isozymes in order to determine differences in their primary structures.