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Showing papers on "Monoamine oxidase B published in 1994"


Journal ArticleDOI
TL;DR: It is concluded that enzyme radioautography with [3H]lazabemide is a reliable high resolution assay for plaque-associated astroglioses in Alzheimer's disease and might, indirectly, be a potential source of cytotoxic free radicals.

344 citations


Journal ArticleDOI
TL;DR: The ability of tissue extracts from various species to deaminate certain amines has been known since the early part of the century and the first demonstration of such an effect was in 1877 by Schmiedeberg (cited by Blaschko and Hawkins, 1952).

167 citations


Journal ArticleDOI
01 Oct 1994-Synapse
TL;DR: The slow turnover of brain MAO B suggests that the current clinical dose of L‐deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated, and the first measurement of the synthesis rate of a specific protein in the living human brain is measured.
Abstract: L-Deprenyl (Selegeline) is an enzyme-activated irreversible inhibitor of monoamine oxidase B (MAO B; EC 1.4.3.4). It is used to treat Parkinson's disease at a dose of 5 mg twice a day. Since enzyme inhibition is irreversible, the recovery of functional enzyme activity after withdrawal from L-deprenyl requires the synthesis of new enzyme. We have measured a 40 day half-time for brain MAO B synthesis in Parkinson's disease and in normal subjects after withdrawal from L-deprenyl. This is the first measurement of the synthesis rate of a specific protein in the living human brain. L-Deprenyl is currently used by 50,000 patients with Parkinson's disease in the United States and its use is expected to increase with reports that it may be beneficial in Alzheimer's disease. The slow turnover of brain MAO B suggests that the current clinical dose of L-deprenyl may be excessive and that the clinical efficacy of reduced dosing should be evaluated. Such an evaluation may have mechanistic importance as well as an impact on reducing the side effects and the costs arising from excessive drug use. © 1994 Wiley-Liss, Inc.1

152 citations


Journal ArticleDOI
TL;DR: Studies with positron emission tomography have shown retention of selegiline in brain areas with high MAO‐B activity, including striatal structures, hippocampus, thalamus, and substantia nigra, as well as in humans.
Abstract: l-Deprenyl (selegiline), an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is rapidly absorbed from the gastrointestinal tract and distributed into tissues. The reaction between MAO and selegiline takes place in two steps. The initial reversible reaction is followed by an irreversible reaction in which selegiline is bound covalently to the flavin part of the enzyme. Studies with positron emission tomography have shown retention of selegiline in brain areas with high MAO-B activity, including striatal structures, hippocampus, thalamus, and substantia nigra. Inhibition of MAO-B in vivo takes place rapidly; for example, platelet MAO is inhibited almost totally within the first 60 minutes after a single 10 mg oral dose of the drug. The recovery of MAO after inhibition depends on the organ and species in question. In rat brain the half-life of recovery in the brain is approximately 8 to 12 days; in rat liver it is shorter, 1 to 3 days. Selegiline is metabolized into l-(-)-desmethylselegiline, l-(-)-methamphetamine, and l-(-)-amphetamine mainly in the liver through the microsomal P-450 system. The stereoselectivity of the metabolites is maintained; no racemic transformation takes place. All three main metabolites are found in human serum, cerebrospinal fluid, and urine, and l-(-)-methamphetamine accounts for most of the metabolite pool. The metabolites are excreted mainly via urine l-(-)-Desmethylselegiline has been shown to be an irreversible inhibitor of MAO-B in the rat and in humans.

119 citations


Journal ArticleDOI
01 Sep 1994-Synapse
TL;DR: It is demonstrated that in older mice, a single dose of MPTP can cause increases of ROS which were associated with subsequent decreases in DA concentrations which suggest that MPTP induced neurotoxicity is age‐dependent and may be mediated by oxidative stress.
Abstract: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes marked depletion of dopamine (DA) levels and reduction in the activity of tyrosine hydroxylase (TH) in the nigrostriatal DA pathway. In the brain, the enzyme monoamine oxidase B converts MPTP to 1-methyl-4-phenylpyridinium (MPP+) which enters DA terminals via DA uptake sites. Within the DA terminals, MPP+ blocks the mitochondrial complex I and causes ATP depletion. This is thought to be the main cause of MPTP-induced terminal degeneration. In addition, reactive oxygen species (ROS) generated after blockade of the complex I as well as those generated due to DA oxidation may participate in MPTP-induced dopaminotoxicity. The present study sought to determine if a single injection of a large dose of MPTP generates ROS. We also sought to determine if these changes as well as changes in DA levels were correlated and age-dependent. Toward that end, we have used C57/B6N male mice that were 22 days or 12 months old. These animals were injected with a single dose of MPTP (40 mg/kg, ip). Animals were sacrificed at various times after drug administration. MPTP produced no significant increase in ROS nor decreases in DA or HVA concentrations in the striatum of the younger mice. However, DOPAC concentrations were significantly decreased from 15-120 min after drug administration. In the older mice, MPTP caused significant increases in ROS from the beginning to the end of the study period. DA concentrations were decreased from 60 min onward. DOPAC concentrations were decreased significantly after 15-120 min while HVA concentrations were significantly increased after 60 and 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)

113 citations


Journal ArticleDOI
TL;DR: Compared the frequency of haplotypes at the MAOA and MAOB loci on the X chromosome in 91 male patients with PD and 129 male controls supports the idea that the MAO genes may be among the herediatary factors that influence susceptibility of individuals to PD.
Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder caused by loss of dopaminergic neurons in the brainstem. Recent studies suggest that several genes may have a role in determining individual susceptibility to this disease, and the degradative enzyme monoamine oxidase (MAO) has been implicated in the disease process. Wide differences in activity levels for both forms of this enzyme (MAO-A and MAO-B) exist in the human population, and levels of both are genetically determined. Here we have compared the frequency of haplotypes at the MAOA and MAOB loci on the X chromosome in 91 male patients with PD and 129 male controls. Alleles were marked using two restriction fragment length polymorphisms (RFLPs), a (GT)n repeat in the MAOA locus, and a (GT)n repeat in the MAOB locus. One particular haplotype marked by the RFLP's at MAOA was three times more frequent in patients with PD as compared with controls, and the overall distribution of these alleles was significantly different (p = 0.03) between these two groups. Another MAOA haplotype was about threefold more common in controls than in patients with PD (p = 0.005). No associations were observed between individual MAOB alleles and the disease state, but the frequency distribution for all alleles was significantly different in the two populations (p = 0.046). These findings support the idea that the MAO genes may be among the hereditary factors that influence susceptibility of individuals to PD.

76 citations


Book ChapterDOI
TL;DR: In the ALS spinal cords an increased number of astrocytes as well as an increased content of MAO-B in reactive species of ast rocytes was demonstrated and a sub-population of reactive astroCytes that contained low levels of MAo-B was observed in spinal sections.
Abstract: A double-staining method was applied to cryosections of human spinal cord from patients who died with amyotrophic lateral sclerosis (ALS) and corresponding controls in order to investigate cellular content of monoamine oxidase B (MAO-B). 3H-L-Deprenyl emulsion autoradiography was used in combination with histochemical methods for the detection of astrocytes and monocytes/microglia. In the ALS spinal cords an increased number of astrocytes as well as an increased content of MAO-B in reactive species of astrocytes was demonstrated. No significant 3H-L-deprenyl binding was observed in cells derived from the mesoderm, e.g. monocytes or microglia. Furthermore, a sub-population of reactive astrocytes that contained low levels of MAO-B was observed in spinal sections. These findings were further substantiated by studies performed on primary astrocyte cultures.

73 citations


Journal Article
TL;DR: It is reported that HPP+ also is toxic to dopaminergic and serotonergic neurons in cultures of embryonic mesencephalic cells, as measured by loss of the ability of exposed cells to accumulate tritium-labeled dopamine and serotonin and by immunochemical staining techniques.
Abstract: It is now generally accepted that the nigrostriatal degenerative properties of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine are mediated by the brain monoamine oxidase B generated 1-methyl-4-phenylpyridinium metabolite (MPP+). In this article, the results are described of ongoing efforts to evaluate the MPP(+)-type neurotoxic potential of the haloperidol (HP)-derived pyridinium metabolite HPP+, a 1,4-disubstituted structural analog of MPP+, which is formed in humans and rats treated with HP. Previous studies in the rat have shown that intrastriatal perfusion of HPP+ leads to the irreversible depletion of striatal dopamine and serotonin. Furthermore, HPP+ was a potent inhibitor of NADH-supported mitochondrial respiration. This article reports that HPP+ also is toxic to dopaminergic and serotonergic neurons in cultures of embryonic mesencephalic cells, as measured by loss of the ability of exposed cells to accumulate tritium-labeled dopamine and serotonin and by immunochemical staining techniques. HPP+ also inhibited the uptake of these labeled neurotransmitters by synaptosomes prepared from mouse neostriata (dopamine) and cortical tissues (serotonin). Because HP is unlikely to be a substrate for brain monoamine oxidase B, the production and accumulation of HPP+ in the brain is probably not comparable to that of MPP+. On the other hand, chronic exposure to HP could result in brain levels of this lipophilic quaternary pyridinium species that might coincide with the late-appearing tardive dyskinesias that are observed in some HP-treated patients months and, more often, years after the initiation of HP therapy.

66 citations


Book ChapterDOI
TL;DR: The enzyme which has come to be known as monoamine oxidase was discovered in liver over 60 years ago as tyramine oxidase and almost 10 years later, Blaschko et al. (1957a,b) established that epinephrine, norepinephrine and dopamine were also substrates for this enzyme.
Abstract: The enzyme which has come to be known as monoamine oxidase was discovered in liver over 60 years ago as tyramine oxidase (Hare, 1928). Almost 10 years later, Blaschko et al. (1957a,b) established that epinephrine, norepinephrine and dopamine were also substrates for this enzyme. Zeller (1938) distinguished monoamine oxidase as different from several other amine oxidases, such as diamine oxidase. Although it was generally assumed that catecholamines were metabolized by MAO, this was not established until isotopically labelled epinephrine and an MAO inhibitor became available. Schayer (1951) found that after administration of N-methyl-14C-epinephrine, only about 50% of the radioactivity appeared in the urine, whereas when the 14C label was incorporated into the β-position on the side chain, almost all of the radioactivity could be recovered. One year later, Zeller et al. (1952) discovered that isonicotinic acid hydrazide (iproniazid) inhibited MAO. When animals pretreated with the MAO inhibitor were administered N-methyl-14C-epinephrine, almost all of the radioactivity was recovered (Schayer et al., 1955), indicating that the enzyme was responsible for the metabolism of about half of the administered catecholamine. Schayer et al. (1952, 1953) had found that five urinary metabolite products of β-labelled-14C-norepinephrine could be separated by paper chromatography, but the chemical structures of these compounds were not known.

65 citations


Journal ArticleDOI
TL;DR: The results suggest that PE can act as a neuromodulator of dopaminergic responses and that MAO‐B inhibitors may potentiate neuronal responses to dopamine via the indirect mechanism of elevation of PE following MAO'B inhibition.
Abstract: 1 (-)-Deprenyl has been shown to potentiate rat striatal neurone responses to dopamine agonists at doses not altering dopamine metabolism Since there are a number of effects of (-)-deprenyl which could result in this phenomenon, we have investigated the effects of MDL 72,145 and Ro 19-6327, whose only common effect with (-)-deprenyl is an inhibition of monoamine oxidase-B (MAO-B), on rat striatal neurone responses to dopamine and on striatal dopamine metabolism 2 Using in vivo electrophysiology, ip injection of either MDL 72,145 or Ro 19-6327 was found to produce a dose-dependent potentiation of striatal neurone responses to dopamine but not gamma-aminobutyric acid 3 Neurochemical investigations revealed that this occurred at doses (025-1 mg kg-1) which, while not affecting levels of dopamine or its metabolites, 3,4-dihydroxyphenylacetic acid or homovanillic acid, did cause a significant, dose-dependent, elevation in striatal levels of the putative neuromodulator, 2-phenylethylamine (PE) 4 Inhibition of PE synthesis by ip injection of the aromatic L-amino acid decarboxylase inhibitor, NSD 1015, produced a reversal of the effects of MDL 72,145 and Ro 19-6327 5 Neurochemical analysis revealed this to occur at a dose of NSD 1015 (10 mg kg-1) selective for reduction of elevated PE levels 6 These results suggest that PE can act as a neuromodulator of dopaminergic responses and that MAO-B inhibitors may potentiate neuronal responses to dopamine via the indirect mechanism of elevation of PE following MAO-B inhibition

50 citations


Journal ArticleDOI
TL;DR: In this article, a short review summarizes characteristics of monoamine oxidase from biochemical and pharmacological points, and then briefly mentions the situation of clinical evaluation studies of deprenyl and lazabemide in terms of antiparkinsonian effects in Japan.
Abstract: Since monoamine oxidase is an enzyme catalyzing bioactive monoamines, inhibitors of monoamines are expected to prolong the activity of monoamines in tissue. Monoamine oxidase type B is an active form in brain, and its preferential substrate is dopamine that is the most constantly reduced monoamine in Parkinson’s disease brain. Therefore, it is natural to expect that monoamine oxidase inhibitors, deprenyl or lazabemide, could exhibit beneficial effects on parkinsonism, i.e. symptomatic effects. This short review summarizes characteristics of monoamine oxidase from biochemical and pharmacological points, and then briefly mentions the situation of clinical evaluation studies of deprenyl and lazabemide in terms of antiparkinsonian effects in Japan.

Journal ArticleDOI
TL;DR: Localization of MAO-containing neurons, fibers and glial cells has been described by recent progress in MAO histochemistry and immunohistochemistry, and increase of 5-HT and DA concentration after inhibition ofMAO-A indicates the possible existence of MAo-A in such neuronal structures.

Journal ArticleDOI
TL;DR: It is suggested that this monoamine oxidase B inhibitor can increase antioxidant enzyme activities in striatum but not in hippocampus in the dog, thus showing brain region selectivity.

Journal ArticleDOI
TL;DR: The correlation analysis between pMAO-B and neuropsychological scores showed a highly significant positive relationship with GBS- emotional impairment, suggesting the importance of platelet MAO- B activity as biological marker also in old- age dementias, namely senile dementia of Alzheimer type.
Abstract: Both low and high platelet MAO-B (pMAO-B) activity is considered an indicator of increased vulnerability in psychopathology. How the activity of this peripheral enzyme can be linked with the sophisticated functions of the central nervous system (CNS) is not clear; in man, evidence exists that the genetic mechanisms determining the size or capacity of the central serotonin system are common to platelet and brain MAO. In the present study pMAO- B activity was evaluated in demented patients suffering from early- onset Alzheimer’s disease (AD), late- onset Alzheimer’s disease (SDAT), vascular dementia (VD), and controls. In these dementia categories, the relationship between pMAO- B activity and clinical features, and between pMAO- B activity and cerebrospinal fluid (CSF) monoamine metabolites (3-methoxy-4-hydroxyphenyl-glycol, MHPG; 5-hydroxy-in-doleacetic acid, 5-HIAA; homovanillic acid, HVA) was also investigated. pMAO-B activity was significantly higher in SDAT patients, compared to controls and AD. Age, as covariate, failed to show any significant effect, and no association was found between pMAO-B activity and CSF monoamine metabolites. The correlation analysis between pMAO-B and neuropsychological scores showed a highly significant positive relationship with GBS- emotional impairment (N=40, r=0.72, p<0.01 in the SDAT group. This result suggests the importance of platelet MAO- B activity as biological marker also in old- age dementias, namely senile dementia of Alzheimer type, where the increased activity of this enzyme might constitute a marker for vulnerability toward behavioural disturbance, i.e., emotional deterioration. (Aging Clin. Exp. Res. 6: 201–207, 1994)

Journal ArticleDOI
TL;DR: Assignments of the 1H- and 13C-NMR data using two dimensional (2D)-NMR techniques showed the active components to be known lichen depsides, confluentic acid and 2'-O-methylperlatolic acid.
Abstract: Monoamine oxidase B (MAO-B) inhibitors were isolated from the bark of a Brazilian plant, Himatanthus sucuuba (SPR.). Assignments of the 1H- and 13C-NMR data using two dimensional (2D)-NMR techniques showed the active components to be known lichen depsides, confluentic acid (1) and 2'-O-methylperlatolic acid (2). The depside (1) showed selective inhibition of MAO-B with IC50 value of 0.22 microM.

Book
01 Jan 1994
TL;DR: The Distribution of Monoamine Oxidases A and B in Normal Human Brain, Karin N. Westlund Effects of Disease and Aging on MonoamineOxidase A andB, Manfred Gerlach, Peter Riederer, and Moussa B. H. Youdim.
Abstract: The Distribution of Monoamine Oxidases A and B in Normal Human Brain, Karin N. Westlund Effects of Disease and Aging on Monoamine Oxidases A and B, Manfred Gerlach, Peter Riederer, and Moussa B. H. Youdim Biochemistry and Mechanism of Action of Monoamine Oxidases A and B, Eimear M. O'Brien and Keith F. Tipton The Structure, Gene, and Promoter Organization of Monoamine Oxidases A and B, Jean Chen Shih, Kevin Chen, Joseph S. Grimsby, Qin-Shi Zhu, and Timothy K. Gallaher Molecular Genetics and Inheritance of Human Monoamine Oxidases A and B, Xandra O. Breakefield, Zheng-Yi Chen, Elizabeth Tivol, Christo Shalish, and Ian W. Craig Role of Monoamine Oxidase Genetics in the Etiology of Parkinson's Disease, Janice H. Kurth and Matthias C. Kurth Multiple Forms of Monoamine Oxidase and Iron: Their Relevance to the Pathology and Treatment of Parkinson's Disease, Moussa B. H. Youdim, Dorit Ben-Shachar, and Peter Riederer A Critical Role for Monoamine Oxidase in Toxin Action in Parkinson's Disease, Peter Jenner Effects of Monoamine Oxidase B Inhibitors on Dopaminergic Function: Role of 2-Phenylethylamine and Aromatic L-Amino Acid Decarboxylase, Augusto V. Juorio, Xin-Min Li, I. A. Paterson, and Alan A. Boulton Inhibition of Monoamine Oxidase B and the Neuroprotective Effects of Selegiline, Kevin T. Finnegan Reduction of Nerve Cell Death by Deprenyl Without Monoamine Oxidase Inhibition, William G. Tatton, Nadine A. Seniuk, William Y. H. Ju, and Karen S. Ansari Monoamine Oxidase Inhibitors as Neuroprotective Therapy, Warren Olanow and Donald B. Calne Selegiline as Symptomatic Treatment for Parkinson's Disease, Abraham Lieberman Monoamine Oxidase Inhibitors in Alzheimer's Disease, Jody Corey-Bloom and Leon J. Thal Role of Monoamine Oxidase Inhibitors in Psychiatry, David J. Houlihan and Samuel Gershon

Journal ArticleDOI
TL;DR: The data obtained indicate that antidepressant activity of tetrindole may be explained by selective inhibition of MAO A, however an apparent discrepancy between competitive manner ofMAO A inhibition in vitro and poor recovery of enzyme activity in vivo does not allow us to decide whether tetrINDole is a "tight-binding" reversible inhibitor or a selective irreversible inhibitor of MAo A.

Book ChapterDOI
TL;DR: The results show that deamination represents the major pathway in the metabolism of newly formed dopamine under in vitro experimental conditions in the rat kidney and only when MAO is inhibited does methylation appear to represent an alternative metabolic pathway.
Abstract: Incubation of slices of rat renal cortex with 50 μM L-DOPA during 15 min resulted in the formation of dopamine and of its deaminated (3,4-dihydroxyphenylacetic acid; DOPAC), methylated (3-methoxytyramine; 3-MT) and deaminated plus methylated (homovanillic acid; HVA) metabolites. The presence of pargyline (100 μM) resulted in a 90% reduction in the formation of DOPAC and HVA; levels of dopamine and 3-MT were found to be significantly increased. A concentration dependent decrease in the formation of methylated metabolites was obtained in the presence of (10, 50 and 100 μM) tropolone (10–50% reduction) and (0.1, 0.5, 1.0 and 5.0 μM) RO 40-7592 (50–95% reduction). Ro 40-7592 was also found to significantly increase DOPAC (20–40%) and dopamine (10–30%) levels, whereas tropolone slightly increased DOPAC (10%) levels. These results show that deamination represents the major pathway in the metabolism of newly formed dopamine under in vitro experimental conditions in the rat kidney. In addition, only when MAO is inhibited does methylation appear to represent an alternative metabolic pathway.

Journal ArticleDOI
TL;DR: Neither conversion of MPTP to its active form, 1-methyl-4-phenyl pyridium (MPP+) by MAO-B nor MPP+ uptake by the dopaminergic transporter are likely to be the rate-limiting step in the toxicity of this compound.

Journal ArticleDOI
TL;DR: Evidence is presented that MAO B may be involved in the sex related effects of MPTP, which depends on its conversion to the 1-methyl-4-phenylpyridinium ion (MPP+) by monoamine oxidase B (MAO B).

Journal ArticleDOI
TL;DR: It is concluded that inhibition of MAO-B has no effect on DA metabolism in the hemi-parkinsonian rat striatum and that 2-phenylethylamine could be involved in the antiparkinsonian action of MAo-B inhibitors.
Abstract: The purpose of this study was to examine whether monoamine oxidase type B (MAO-B) has a role in striatal dopamine metabolism in animals with a unilateral lesion of the medial forebrain bundle, and whether 2-phenylethylamine (PE) could have a role in amplification of dopamine (DA) responses in DA depleted striatum. Inhibition of MAO-B did not alter DA metabolism in lesioned striata. PE accumulation decreased with loss of DA as long as there was no DA dysfunction. In lesioned striata with dysfunction of DA transmission at the synaptic level, PE accumulation increased, suggesting a compensatory increase in PE synthesis. This increase in PE levels does not appear to be mediated by an increase in the total striatal aromatic L-amino acid decarboxylase (AADC) activity. We conclude that inhibition of MAO-B has no effect on DA metabolism in the hemi-parkinsonian rat striatum and that PE could be involved in the antiparkinsonian action of MAO-B inhibitors.

Journal ArticleDOI
TL;DR: The results presented here show that the fraction of newly‐formed dopamine which leaves the compartment where the synthesis has occurred is a constant source for deamination into DOPAC, providing evidence favouring the view that MAO‐A is the main form of the enzyme involved in this process.
Abstract: 1. The influence of pargyline and of selective inhibitors of type A and B monoamine oxidase (MAO), Ro 41-1049 and Ro 19-6327 respectively, on the outflow of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) in slices of rat renal cortex loaded with exogenous L-3,4-dihydroxyphenylalanine (L-DOPA) was examined. Dopamine and DOPAC in the tissues and in the effluent were assayed by means of h.p.l.c. with electrochemical detection. 2. The levels of newly-formed dopamine and DOPAC in the perifusate decreased progressively with time. In control conditions, DOPAC/dopamine ratios in the perifusate were 3 to 5 fold those in the tissue and were found to increase progressively with time. The addition of pargyline (100 microM), produced a marked decrease in the outflow levels of DOPAC (45 to 54% reduction) and significantly increased the levels of dopamine in the effluent (102 to 158% increase); DOPAC/dopamine ratios in the perifusate remained stable throughout the perifusion and were similar to those found in the tissues. The addition of the MAO-A inhibitor Ro 41-1049 to the perifusion fluid also significantly decreased DOPAC outflow (41% to 54% reduction) and increased dopamine outflow (19% to 80% increase). In the presence of Ro 41-1049 DOPAC/dopamine ratios in the perifusate were lower (P < 0.01) than in controls; in contrast with the effect of pargyline, this ratio was found to increase (P < 0.01) throughout the perifusion period. Ro 19-6327 did not reduce the outflow of DOPAC, but significantly increased (by 40-60%) that of dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal ArticleDOI
TL;DR: The discovery that inhibitors of monoamine oxidase (EC 1.3.4.; MAO) are antidepressants has resulted in the synthesis of large numbers of inhibitors, several of which have proved to be valuable in clinical use.
Abstract: Introduction The discovery that inhibitors of monoamine oxidase (EC 1.4.3.4.; MAO) are antidepressants (see [ l ] for a review) has resulted in the synthesis of large numbers of inhibitors, several of which have proved to be valuable in clinical use. Such work was given added impetus when it was recognized that there are two monoamine oxidases in most mammalian tissues, MAO-A and MAO-B, with different substrate and inhibitor specificities. 5-Hydroxytryptamine (5-HT; also known as serotonin) is a preferred substrate for MAO-A and the trace amine 2-phenethylamine is a preferred substrate for MAO-B. Both enzymes from human brain catalyse the oxidation of dopamine, noradrenaline and tyramine (see [2,3] for reviews). Inhibitors of MAO-A have been shown to be effective antidepressants (see [ l]), whereas inhibitors of MAO-B appear to be of value in the treatment of Parkinson’s disease, either in combination with L-dopa [4] or, perhaps, alone 151. It has also been suggested that at least some inhibitors of MAO-B may be capable of either protecting or rescuing neurons from potentially lethal damage (see [6,7]). A particular problem with the use of MA0 inhibitors as antidepressants has been that they can give rise to strong hypertensive responses following the ingestion of some foods and beverages. This was shown to be a result of the relatively high concentrations of amines, often tyramine, in the ingested material (see [ 1,s101). Because some cheeses are particularly rich in tyramine, this effect has become known as the ‘cheese reaction’. However, many other foods and beverages contain amines which can interact in this way, and because of the nature of some of the foods involved and the lack of any legislation controlling the tyramine contents, the quantities present can be extremely variable (see [%lo]). Although tyramine is a good substrate for both forms of the enzyme, it is only those inhibitors that affect MAO-A that give rise to this reaction. This is because MAO-A predominates in the human intestine and stomach, which are the first lines of defence against ingested amines (see [ 1 11). Since the crystal structures of the MAOs have yet to be determined, information for the design of

Journal ArticleDOI
TL;DR: In mice, IFO increased the striatal concentrations of 2-phenylethylamine and showed almost the same protective efficacy as L-deprenyl against the lethality and striatal dopamine depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Journal ArticleDOI
TL;DR: Selective MAO‐B inhibitors could represent a unique class of drugs, having symptomatic actions with possible neuroprotective and neurorescue actions in one, and may herald a neuroprot protective approach to the treatment of Parkinson's disease.
Abstract: The acetylenic selective monoamine oxidase (MAO) type B suicide inhibitor, l-deprenyl (l-selegiline), has proved to be a useful adjuvant to L-dopa therapy and monotherapy of Parkinson's disease. Although not all features of its antiParkinson action are known, studies that used brains obtained at autopsy from patients who took l-deprenyl show that the selective inhibition of MAO-B with a concomitant increase of phenylethylamine and dopamine, but not of serotonin or noradrenaline, in the basal ganglia may be reponsible for its mode of action. The increased life expectancy noted in patients with Parkinson's disease who received long-term therapy (9 years in an uncontrolled study) is another unexpected feature of the drug. These exciting data, if confirmed in other long-term clinical trials, may herald a neuroprotective approach to the treatment of this degenerative disease. More recent studies indicate that Parkinson's disease may eventually turn out to be a neurotoxic event resulting from oxidative stress- induced free radical species in the substantia nigra. Thus selective MAO-B inhibitors could represent a unique class of drugs, having symptomatic actions with possible neuroprotective and neurorescue actions in one

Journal ArticleDOI
TL;DR: In the human brain, monoamine-derived 6,7-dihydroxy-1,2-3,4-tetrahydroisoquinolines and 1,2,3, 4-TetrahYDroisoquolines have been identified and their enzymatic methylation into N(2)-methylisoquinolineines has been confirmed.

Journal ArticleDOI
TL;DR: The results are discussed in terms of possible catalytic pathways for the MAO-B catalyzed oxidation of 1,4-disubstituted-1,2,3,6- tetrahydropyridines.
Abstract: Previous studies have established that 1-cyclopropyl-4-phenyl-1,2,3,6- tetrahydropyridine (6) is an efficient time and concentration dependent inhibitor of the flavin containing enzyme monoamine oxidase B (MAO-B). This behavior is consistent with a proposed mechanism based inactivation pathway initiated by transfer of one of the nitrogen nonbonding pairs of electrons to the oxidized flavin cofactor to generate an amine radical cation intermediate. Subsequent opening of the strained cyclopropylamine ring is thought to lead to a primary carbon centered radical that inactivates the enzyme by covalent modification of the flavin or an essential active site functionality. We now have examined the MAO-B inactivator and substrate properties of 4-benzyl-1-cyclopropyl-1,2,3,6-tetrahydropyridine (11). This compound also is a time and concentration dependent inhibitor of MAO-B. Unexpectedly, however, compound 11 proved to be an excellent MAO-B substrate. These results are discussed in terms of possible catalytic pathways for the MAO-B catalyzed oxidation of 1,4-disubstituted-1,2,3,6- tetrahydropyridines.


Journal ArticleDOI
TL;DR: There was no association between a low vitamin B12 level and high MAO-B activity in a sample of patients, who are living in a geriatric hospital where the balanced nutrition of inpatients is controlled by diet assistants.

Journal ArticleDOI
TL;DR: Results show that in the guinea pig striatum inhibition of monoamine oxidase B by (-)-deprenyl impairs the metabolism of dopamine in the whole tissue but does not produce a marked increase in extracellular dopamine.