Showing papers on "Monoamine oxidase B published in 1996"

Inhibition of monoamine oxidase B in the brains of smokers

Abstract: The massive health problem associated with cigarette smoking is exacerbated by the addictive properties of tobacco smoke and the limited success of current approaches to cessation of smoking. Yet little is known about the neuropharmacological actions of cigarette smoke that contribute to smoking behaviour, or why smoking is so prevalent in psychiatric disorders and is associated with a decreased risk of Parkinson's disease. Here we report that brains of living smokers show a 40% decrease in the level of monoamine oxidase B (MAO B; EC 1.4.3.4) relative to non-smokers or former smokers. MAO B is involved in the breakdown of dopamine, a neurotransmitter implicated in reinforcing and motivating behaviours as well as movement. MAO B inhibition is therefore associated with enhanced activity of dopamine, as well as with decreased production of hydrogen peroxide, a source of reactive oxygen species. We propose that reduction of MAO B activity may synergize with nicotine to produce the diverse behavioural and epidemiological effects of smoking.

Monoamine oxidase inhibitors. An update on drug interactions.

Abstract: After initial enthusiasm, the use of monoamine oxidase inhibitors (MAOIs) has been limited by the wide range of MAOI-drug and MAOI-food interactions that are possible, particularly with sympathomimetic medications or tyramine-containing foods, resulting in hypertensive reactions. Despite their clinical benefits, this has led to a reduction in use of such medications.

Modulation of gene expression rather than monoamine oxidase inhibition (-)-Deprenyl-related compounds in controlling neurodegeneration

Abstract: (-)-Deprenyl has been used to irreversibly inhibit monoamine oxidase B (MAO-B) in Parkinson's disease (PD) and Alzheimer's disease (AD) as a possible means of improving dopaminergic neurotransmission or of reducing neuronal necrosis caused by oxidative radical damage. Recent research in tissue culture and animal models has shown that (-)-deprenyl can reduce neuronal apoptosis caused by a variety of agents, in a variety of neuronal subtypes through a mechanism(s) that does not require MAO-B inhibition. Studies using general P450 blockers have shown that one of the principal metabolites of (-)-deprenyl, (-)-desmethyldeprenyl, mediates the antiapoptotic action. Other research has shown that (-)-deprenyl can induce altered expression of a number of genes in preapoptotic neurons both in vitro and in vivo, including the genes for superoxide dismutase (SOD) 1 and 2, BCL-2 and BCL-XL, nitric oxide synthase, c-JUN, and nicotinamide adenine dinucleotide dehydrogenase. Antiapoptosis by (-)-deprenyl is associated with a prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons, which has been shown to occur early in apoptosis and is likely an initiating factor. The above changes in gene expression appear to reduce oxidative radical damage to mitochondria and maintain mitochondrial permeability, thereby blocking mitochondrial "signals" that initiate apoptosis. In situ evidence suggests that apoptosis contributes to neuronal death in a number of neurodegenerative diseases. If apoptosis is critical to the progression of one or more human neurodegenerative diseases, then transcriptionally active agents such as (-)-desmethyldeprenyl may be of value in treating the diseases. The kinetics of (-)-deprenyl metabolism, however, and its biodistribution after oral administration, make it unlikely that the antiapoptotic action has played a major role in benefits found for the drug in PD and AD to date.

Pharmacology of selegiline

Abstract: The acetylenic selective monoamine oxidase (MAO) type B suicide inhibitor selegiline (previously called L-deprenyl) has proved to be a useful adjuvant to levodopa therapy and monotherapy of Parkinson's disease (PD). Selegiline is readily absorbed from the gastrointestinal tract and rapidly enters the brain and spinal cord following oral administration. The drug binds to brain regions with a high MAO-B content, such as the thalamus, the striatum, the cortex, and the brainstem. It is extensively metabolized in humans, mainly in the liver, to form desmethylselegiline and methamphetamine, which are further metabolized to amphetamine. Eighty-six percent of the 10-mg dose was recovered in the urine within 24 hours. These data suggest that accumulation of metabolites does not occur. Although not all features of its anti-PD action are known, studies using brain obtained at autopsy from patients who had been treated with 10 mg of selegiline showed that selective inhibition of MAO-B, with the concomitant increase of phenylethylamine and dopamine (DA) but not of serotonin or noradrenaline, in the basal ganglia may be regarded as its mode of action. The protective effects afforded by selegiline in PD, resulting in a delayed need for levodopa therapy, have been variously interpreted in terms of the involvement of an endogenous neurotoxin or an oxygen free radical mechanism (oxidative stress) in the development of PD. However, although many different hypotheses have been advanced and recent findings have emphasized the significance of oxidative stress in the pathogenesis of the disease, the cause of chronic nigral cell death and the underlying mechanisms remain, as yet, elusive. Therefore, there is no clear knowledge regarding an understanding of the reported effects of selegiline on the progression of PD. Nevertheless, selegiline might be expected to have some protective effects in reducing the production of potentially neurotoxic compounds resulting in the MAO-catalyzed oxidation of DA. In addition, some evidence suggests both an indirect (via induction of radical-scavenging enzymes) and a direct antioxidant function for selegiline. On the other hand, the reported protective effect of selegiline might also receive a contribution from the diminished potentiation of the N-methyl-D-aspartate receptor by the polyamine binding site. Finally, the effects of selegiline might also involve preventing, or perhaps to some extent reversing, the decline in resistance normally associated with cellular aging because of its neurotrophine-like action. However, even in the early clinical stage of PD, the sequence of events leading to nigral cell death may be too far advanced for selegiline to exhibit its maximum potential.

Association of monoamine oxidase A alleles with alcoholism among male Chinese in Taiwan

Abstract: Objective : The role of monoamine oxidase (MAO) in alcoholism was assessed by genetic association studies separately in five ethnic groups in Taiwan. Method : Restriction fragment length polymorphisms (RFLP) and dinucleotide repeat polymorphisms (DNRP) were used to determine MAOA and MAOB alleles in male alcoholic patients and nonalcoholic comparison subjects among Han Chinese and four aboriginal groups. Results : Significant associations of alcohol dependence with MAOA alleles (RFLP and DNRP) were found among the Han Chinese, but not among the aboriginal groups. No significant association with MAOB DNRP alleles was found in any group. Conclusions : Genetic heterogeneity may underlie alcoholism among different ethnic groups in Taiwan, and MAOA mutations may play a role in susceptibility to alcoholism among Han Chinese.

Investigation on the Structure of the Active Site of Monoamine Oxidase‐B by Affinity Labeling with the Selective Inhibitor Lazabemide and by Site‐Directed Mutagenesis

Abstract: The structural features of the active site of human monoamine oxidase B (MAO-B) were investigated by affinity labeling and site-directed mutagenesis. The pseudosubstrate inhibitor N-[2-aminoethyl]-5-chloro-2-pyridine carboxamide HCl (lazabemide) can be irreversibly linked to MAO-B by reduction of the enzyme-inhibitor complex with NaBH(3)CN. Analysis of the flavin spectrum of [(3)H]lazabemide-labeled human MAO-B indicated that insertion of the inhibitor did not occur into the isoalloxazine ring of FAD. After trypsin digestion and HPLC peptide mapping of the radiolabeled enzyme, two labeled peptides were observed. Sequence analysis showed that both peptides started at Val371 of human MAO-B. These results indicate that [(3)H]lazabemide is incorporated into the MAO-B peptide stretch containing the FAD-modified Cys397. The function of putative active-site residues contained in this region was investigated by site-directed mutagenesis and expression of the mutant proteins in HEK-293 cells. Substitution of His382 of MAO-B with an Arg greatly reduced the enzymic activity, suggesting that this residue may represent a nucleophile relevant for the MAO-B catalytic mechanism. Whereas it has been shown that mutation of Cys389 with a Ser residue does not markedly affect the activity of the enzyme [Wu, H.-F., Chen, K. and Shih, J.C. (1993) Mol. Pharmacol. 43, 888-893] the mutant carrying an Ala at this position was virtually inactive. Conversely, substitution of Lys386 (to Met) and Ser394 (to Ala) did not markedly modify the kinetic properties of the enzyme. We also report that mutation of MAO-B Thr158 (to Ala) resulted in a dramatic loss of enzymic activity. [on SciFinder (R)]

maoB, a gene that encodes a positive regulator of the monoamine oxidase gene (maoA) in Escherichia coli.

Abstract: The structural gene for copper- and topa quinone-containing monoamine oxidase (maoA) and an unknown amine oxidase gene have been located at 30.9 min on the Escherichia coli chromosome. Deletion analysis showed that the unknown gene was located within a 1.1-kb cloned fragment adjacent to the maoA gene. The nucleotide sequence of this fragment was determined, and a single open reading frame (maoB) consisting of 903 bp was found. The gene encoded a polypeptide with a predicted molecular mass of 34,619 Da which was correlated with the migration on a sodium dodecyl sulfate-polyacrylamide gel. The predicted amino acid sequence of the MaoB protein was identical to the NH2-terminal amino acid sequence derived by Edman degradation of the protein synthesized under the self-promoter. No homology of the nucleotide sequence of maoB to the sequences of any reported genes was found. However, the amino acid sequence of MaoB showed a high level of homology with respect to the helix-turn-helix motif of the AraC family in its C terminus. The homology search and disruption of maoA on the chromosome led to the conclusion that MaoB is a transcriptional activator of maoA but not an amine oxidase. The consensus sequence of the cyclic AMP-cyclic AMP receptor protein complex binding domain was adjacent to the putative promoter for the maoB gene. By use of lac gene fusions with the maoA and maoB genes, we showed that the maoA gene is regulated by tyramine and MaoB and that the expression of the maoB gene is subject to catabolite repression. Thus, it seems likely that tyramine and the MaoB protein activate the transcription of maoA by binding to the regulatory region of the maoA gene.

Synthesis and selective monoamine oxidase B-inhibiting properties of 1-methyl-1,2,3,6-tetrahydropyrid-4-yl carbamate derivatives: potential prodrugs of (R)- and (S)-nordeprenyl.

Abstract: The results of previous studies have established that the monoamine oxidase-catalyzed oxidation of 1-methyl-1,2,3,6-tetrahydropyridyl derivatives bearing heteroatom substituents at C-4 generates 2,3-dihydropyridinium intermediates that undergo spontaneous hydrolysis to release the C-4 substituent and form the amino enone 1-methyl-2,3-dihydro-4-pyridone. We have attempted to adapt this metabolic pathway to the preparation of amine-containing prodrugs that may target the central nervous system which is rich in monoamine oxidase A and B. In this paper we report the synthesis and the in vitro and in vivo metabolic fate of the tetrahydropyridyl carbamate derivatives which are designed to release (S)- and (R)-nordeprenyl. These carbamates are selective monoamine oxidase A substrates. An ex vivo assay has shown that the R-enantiomer is an effective and selective inhibitor of brain mitochondrial monoamine oxidase B.

Mutational analysis of the human MAOA gene.

Abstract: The monoamine oxidases (MAO-A and MAO-B) are the enzymes primarily responsible for the degradation of amine neurotransmitters, such as dopamine, norepinephrine, and serotonin. Wide variations in activity of these isozymes have been reported in control humans. The MAOA and MAOB genes are located next to each other in the p11.3-11.4 region of the human X chromosome. Our recent documentation of an MAO-A-deficiency state, apparently associated with impulsive aggressive behavior in males, has focused attention on genetic variations in the MAOA gene. In the present study, variations in the coding sequence of the MAOA gene were evaluated by RT-PCR, SSCP, and sequencing of mRNA or genomic DNA in 40 control males with >100-fold variations in MAOA activity, as measured in cultured skin fibroblasts. Remarkable conservation of the coding sequence was found, with only 5 polymorphisms observed. All but one of these were in the third codon position and thus did not alter the deduced amino acid sequence. The one amino acid alteration observed, lys{r_arrow}arg, was neutral and should not affect the structure of the protein. This study demonstrates high conservation of coding sequence in the human MAOA gene in control males, and provides primer sets which can be used to searchmore » genomic DNA for mutations in this gene in males with neuropsychiatric conditions. 47 refs., 1 fig., 2 tabs.« less

Observation of a flavin semiquinone in the resting state of monoamine oxidase B by electron paramagnetic resonance and electron nuclear double resonance spectroscopy.

Abstract: Monoamine oxidase (MAO) plays an essential role in the regulation of various neurotransmitter and xenobiotic amines. Inhibitors of MAO have been employed in the treatment of depression and as adjuncts in Parkinson's disease therapy. X-Band and Q-band electron paramagnetic resonance (EPR) and electron nuclear double resonance (ENDOR) spectroscopic techniques are employed to characterize a signal assigned as a stable red anionic semiquinone radical in the resting state of MAO B. It is shown that the radical signal is not affected during substrate (either benzylamine or phenylethylamine) turnover, by anaerobic incubation with substrate, or by covalent modification of the active site flavin cofactor in the catalytically active dimer. Upon denaturation, however, the semiquinone absorbances and EPR signals are lost. Photoreduction of the native enzyme in the presence of ethylenediaminetetraacetate generates an EPR signal that is not the same as that obtained in the resting state and shows different proton ENDOR signals. These results suggest that the two flavin prosthetic groups that exist in catalytically active monoamine oxidase B are physically distinct.

Genetic elevation of monoamine oxidase levels in dopaminergic PC12 cells results in increased free radical damage and sensitivity to MPTP

Abstract: Production of hydrogen peroxide as a by-product of the breakdown of catecholamines by the enzyme monoamine oxidase (MAO) has been hypothesized to contribute to the increased proclivity of dopaminergic neurons for oxidative injury. We established clonal dopaminergic PC12 cell lines which have elevated MAO activity levels resulting from transgenic expression of the B isoform of the enzyme. Both MAO-A and MAO-B have relatively equivalent affinities for dopamine, and since PC12 primarily express the A and not the B form of the enzyme, this allowed us to distinguish the transgenic MAO activity in these cells from endogenous using the MAO-B specific substrate PEA. Elevation of MAO activity levels in the MAO-B+ cells resulted in higher levels of both free radicals and free radical damage compared with controls. In addition, increased MAO-B levels within PC12 cells caused a dose-dependent increase in sensitivity to the toxin MPTP. Our data suggests that oxidation of catecholamines by MAO can contribute to free radical damage in catecholaminergic neurons and that the low MAO-B activity levels found endogenously in these cells likely accounts for their relative resistance to MPTP toxicity.

Selegiline and lymphocyte superoxide dismutase activities in Parkinson's disease

Abstract: Superoxide dismutases (SODs) are metalloenzymes that detoxify superoxide radicals, and occur in cytosolic (Cu,Zn-SOD) and mitochondrial (Mn-SOD) forms in multiple tissues, including brain. A neuroprotective effect against oxide stressor exposures may be provided by SOD, although excessive enzyme activity can produce cell injury by formation of hydroxyl radical from hydrogen peroxide. We measured Cu,Zn-SOD and Mn-SOD activities in peripheral lymphocytes of 43 newly diagnosed idiopathic Parkinson's disease (PD) cases and 62 age- and sex-matched controls free of neurodegenerative disorders. Significant excesses of both SOD forms were found among PD cases compared with controls; however, the excesses were found exclusively among PD patients treated with the monoamine oxidase inhibitor selegiline (L-deprenyl). Enzyme-linked immunosorbent assays (ELISAs) confirmed that the activity excesses were due to increased protein rather than more highly reactive enzymes in lymphocytes of PD cases. Our findings clearly indicate the importance of selegiline on measured Cu,Zn-SOD and Mn-SOD activity in peripheral lymphocytes. Characterizing a possible therapeutic value of SOD will require longitudinal assessments of SOD in relation to PD progression.

Inactivation of cytochrome P4502B1 by the monoamine oxidase inhibitors R-(-)-deprenyl and clorgyline.

Abstract: The monoamine oxidase inhibitors R-(-)-deprenyl (deprenyl) and clorgyline inactivated the 7-ethoxy-4-trifluoromethylcoumarin O-deethylase activity of purified cytochrome P4502B1 (P4502B1) in a reconstituted system containing P4502B1, NADPH-cytochrome P450 oxidoreductase, and L-alpha-phosphatidylcholine dilauroyl as the lipid. The inactivation was time- and concentration-dependent. The inactivation required NADPH, demonstrated saturation kinetics, and no lag time for inactivation was observed. The inactivation was not affected by the presence of an excess exogenous nucleophile, such as glutathione. Deprenyl exhibited a KI (concentration of inactivator required for half-maximal inactivation) of 1.05 microM, and clorgyline had a KI of 1.5 microM. The maximum rate of inactivation of the enzyme at saturating levels of inactivator (kinactivation) was 0.23 min-1 for deprenyl and 0.28 min-1 for clorgyline. The partition ratio for deprenyl and clorgyline was between 2 and 3. Studies on the isozyme specificity of these compounds in microsomes from rats pretreated with specific inducers demonstrate that the inactivation was relatively specific for the major phenobarbital-inducible isozyme, P4502B1, because significant inactivation of P4501A1 and P4502E1 was not observed. When the purified P4502B1 in the reconstituted system was incubated with either inactivator in the presence of NADPH, there was approximately a 60-70% loss in spectrally detectable P450 over 5 min at a 1:21 ratio of P450 to inactivator. However, at this ratio of enzyme to inactivator, there was > 90% loss of the O-deethylase activity. This loss in enzyme activity was irreversible, and the protein did not regain activity after dialysis or extensive washing to remove excess inactivator.

Monoamine Oxidase B Inhibitors

Abstract: Specific inhibitors of monoamine oxidase type B (MAO-B) constitute a novel and expanding pharmacological class. At present, only one compound from this class is marketed, selegiline (deprenyl). Other MAO-B inhibitors that are in various stages of development include lazabemide and mofegiline, which are differentiated from selegiline by their greater specificity for MAO-B and the absence of active metabolites.

Role of selegiline in combination therapy of Parkinson's disease

Abstract: Selegiline (earlier called deprenyl) is an irreversible inhibitor of monoamine oxidase type B (MAO-B). The inhibition is based on a covalent, irreversible bond formed between the propargyl group of selegiline and the flavin part of MAO. [1] In low doses (0.25 mg/kg subcutaneously in rats and 10 mg daily in humans) selegiline is a potent and selective inhibitor of MAO-B. [2,3] MAO-B inhibition can be easily tested in humans by measuring the MAO activity of platelets, as about 95% of MAO activity in platelets is of type B. [4] Because of its selectivity it is free of the "cheese effect," i.e., increase of blood pressure after food rich in tyramine, which is a substrate for MAO-A. [5,6] In rodents selegiline does not have marked effects on the concentrations of the main catecholamines, dopamine or noradrenaline, because MAO-A is the predominant form of MAO in rodent brain. [7] In primate brain MAO-B is the predominant form with regard to degradation of dopamine, and therefore selegiline causes an increase of dopamine and decrease of 3,4-dihydroxyphenylacetic acid (DOPAC) in caudate in monkey brain. [8] In parkinsonian rat models, such as the 6-hydroxy dopamine (6-OHDA) model in which substantia nigra has been unilaterally destroyed with the toxin, selegiline enhances the effect of levodopa. [9-11] Nonselective MAO inhibitors had earlier been reported to cause some benefit but unacceptable adverse events in the treatment of Parkinson's disease (PD), [12,13] and therefore it was logical to test selegiline in this disease. The early findings by Birkmayer et al. [14] showed that selegiline potentiated the efficacy of levodopa in the treatment of PD patients and was well tolerated. This preliminary finding was followed by a number of trials assessing selegiline therapy in PD. The studies first concentrated on the use of selegiline in advanced PD, i.e., patients with …

Pharmaceutical compositions comprising monoamine oxidase b inhibitors

Abstract: This invention relates to a pharmaceutical composition for oral administration comprising a carrier and, as an active ingredient, a monoamine oxidase B inhibitor, characterised in that the composition is formulated to promote pre-gastric absorption of said monoamine oxidase B inhibitor. A process for preparing such a composition and the use of such a composition for the treatment of Parkinson's disease, the treatment and/or prophylaxis of depression and the treatment and/or prophylaxis of Alzheimer's disease are also provided.

Assessment of structural requirements for the monoamine oxidase-B-catalyzed oxidation of 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives related to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Abstract: The monoamine oxidase B (MAO-B) substrate properties and distance measurements along the N1−C4 axis of 38 1,4-disubstituted-1,2,3,6-tetrahydropyridine derivatives, including seven newly synthesized MPTP analogs, were used to define the maximum size that can be accommodated by the MAO-B active site. Only those compounds measuring less than 12 A displayed significant MAO-B substrate properties. The behavior of various 4-substituted-1-cyclopropyltetrahydropyridine analogs also is discussed in terms of this N1−C4 distance parameter in an effort to understand factors which contribute to their substrate vs inactivator properties. We conclude that this distance parameter will predict the majority of substrates vs nonsubstrates with this class of compound.

Levodopa and deprenyl treatment effects on peripheral indices of oxidant stress in Parkinson's disease

Abstract: Although the cause of Parkinson's disease (PD) remains unexplained, oxidant stress is hypothesized as a major pathogenic factor. [1,2] The selective destruction of the substantia nigra is primarily responsible for the motor deficits that occur in this condition. This midbrain nucleus contains high concentrations of the catecholamine neurotransmitter dopamine, which is postulated to be a potential source of oxidant stress. This theoretically occurs as a consequence of two of the major routes by which dopamine is metabolized. Both enzymatic oxidation by monoamine oxidase (MAO) and nonenzymatic autoxidation of dopamine generate oxyradical byproducts. [1,2] As evidence, the lipid peroxidation product, malondialdehyde, is elevated in the degenerating substantia nigra of patients with PD. [3] It follows from this hypothesis that exogenous replacement therapy with the dopamine precursor levodopa is detrimental, since this elevates dopamine levels, potentially adding to the oxidant stress. [1,4] Protection against one route of oxidative damage from dopamine (and levodopa therapy) may theoretically occur with the administration of deprenyl (selegiline). [1,2,5] This drug blocks the B form of MAO, one of the two major MAO isozymes. Indirect evidence from a large multicenter clinical trial [5] was interpreted as consistent with a neuroprotective effect from deprenyl and attributed to a reduction of oxidative damage generated via MAO metabolism of dopamine. [6] However, others suggest that the data are consistent with the action of deprenyl being merely symptomatic. [7,8] The pathogenic process underlying PD may not, however, be confined to the brain or even the nervous system. Abnormalities in oxidative phosphorylation are present in circulating platelets [9-11] as well as muscle. [12-15] Two studies have reported elevated concentrations of the lipid peroxidation product malondialdehyde in serum or plasma of patients with PD. [16,17] Dermatologic findings (seborrheic dermatitis) are a recognized accompanying manifestation of PD, [18] an observation also consistent with extracerebral …

Pharmacokinetic-pharmacodynamic interactions between two selective monoamine oxidase inhibitors: moclobemide and selegiline

Abstract: The objectives of this study were to assess potential pharmacokinetic and pharmacodynamic interactions between moclobemide and selegiline. Two groups of 12 healthy male and female subjects were treated with 200 mg moclobemide or 5 mg selegiline b.i.d. for 16 days. On study day 8, the alternative active drug or placebo was added to the respective treatments. Concentration-time profiles of moclobemide and two of its main metabolites and 3,4-dihydrox/phenylglycol (DHPG, a norepinephrine metabolite), 5-hydroxy-indoleacetic acid (HIAA, a serotonin metabolite), and 3,4-dihydroxyphenylacetic acid (DOPAC, a dopamine metabolite) in plasma as well as MAO-B activity and serotonin concentration in platelets were determined at steady state during monotreatment and combined treatment. The pharmacokinetic parameters of moclobemide and its metabolites changed on multiple dosing but were not influenced to a relevant extent by concomitant administration of selegiline. The measured pharmacodynamic parameters, expressed as the maximum effect on a study day and the area under the effect-time curve, characterized the drugs' influence on peripheral neurotransmitter metabolism. The most reliable variables to assess inhibition of MAO-A and -B in humans proved to be DHPG in plasma and serotonin in platelets and MAO-B activity in platelets, respectively. Several variables (DHPG, platelet serotonin) suggested that selegiline has some MAO-A inhibitory activity. This became particularly apparent upon addition of selegiline to moclobemide treatment; i.e., the effects of combined moclobemide and selegiline treatment were statistically greater than those of moclobemide monotreatment. Moclobemide alone exerted a slight inhibition of platelet MAO-B activity. The reported pharmacodynamic interactions are not considered to be clinically relevant. However, due to the previously found supraadditive tyramine potentiation upon simultaneous treatment, moclobemide and selegiline should only be combined when applying dietary restrictions with respect to tyramine.

Electrophysiological effects of monoamine oxidase inhibition on rat midbrain dopaminergic neurones: an in vitro study

Abstract: 1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 microM, decreased or abolished the spontaneous firing discharge of the principal neurons in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine D1 receptor antagonist, SCH 23390 (1-3 microM) did not counteract the induced inhibition of the firing rate. 4 The inhibitor for the MAO A, clorgyline (30-100 microM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 microM), was applied. Lower concentrations of both drugs (300 nM-10 microM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors.

Visualization of monoamine oxidase in human brain

Abstract: Monoamine oxidase is a flavin enzyme which exists in two subtypes, MAO A and MAO B. In human brain MAO B predominates and is largely compartmentalized in cell bodies of serotonergic neurons and glia. Regional distribution of MAO B was determined by positron computed tomography with volunteers after the administration of deuterium substituted [11C]L-deprenyl. The basal ganglia and thalamus exhibited the greatest concentrations of MAO B with intermediate levels in the frontal cortex and cingulate gyrus while lowest levels were observed in the parietal and temporal cortices and cerebellum. We observed that brain MAO B increases with are in health normal subjects, however the increases were generally smaller than those revealed with post-mortem studies.