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PubMed1991

Prevention of H2O2 generation by monoamine oxidase protects against CNS O2 toxicity.

Toxicity to the central nervous system (CNS) by hyperbaric oxygen (HBO) presumably relates to increased production of reactive oxygen species. The sites of generation of reactive oxygen species during HBO, however, have not been fully characterized in the brain. We investigated the relationship between regional generation of hydrogen peroxide (H2O2) in the brain in the presence of an irreversible inhibitor of catalase, aminotriazole (ATZ), and protection from CNS O2 toxicity by a monoamine oxidase (MAO) inhibitor, pargyline. At 6 ATA of oxygen, pargyline significantly protected rats from CNS O2 toxicity whereas ATZ enhanced O2 toxicity. In animals pretreated with ATZ, HBO inactivated 21-40% more catalase than air exposure in the six brain regions studied. Because ATZ-mediated inactivation of catalase was H2O2 dependent, the decrease in catalase activity during hyperoxia was proportional to the intracellular production of H2O2. Pargyline, administered 30 min before HBO, inhibited MAO by greater than 90%, prevented ATZ inhibition of catalase activity during HBO, and reversed the augmentation of CNS O2 toxicity by ATZ. These findings indicate that H2O2 generated by MAO during hyperoxia is important to the pathogenesis of CNS O2 toxicity in rats.

Amitrole↗
PubMed2006

Monoamine oxidase and tobacco dependence.

Tobacco smoking is a leading cause of preventable death around the world, and there are major public health and research efforts in many countries aimed at reducing its usage. However, the molecular mechanisms underlying tobacco dependence are still not completely understood. Nicotine's action on nicotinic acetylcholine receptors, and the downstream release of dopamine, is believed to be the major pathway underlying tobacco dependence. However there is mounting evidence indicating that non-nicotinic components of tobacco smoke also play a role by inhibiting monoamine oxidase (MAO) and subsequently altering neurotransmitter levels. This article provides a review of the current knowledge of the association between MAO and tobacco dependence and suggests that further research into this topic is likely to lead to more effective pharmacotherapies for smoking cessation.

Animals↗
PubMed1996

Does monoamine oxidase inhibition by pargyline increase extracellular dopamine concentrations in the striatum?

The present study examined the possibility that pargyline-induced stimulation of dopamine neurotransmission in the striatum measured by intracerebral microdialysis may be related to alterations in the function of dopamine nerve terminals in close proximity to the implanted microdialysis probe. Changes in extracellular concentrations of dopamine were determined bilaterally in the striata of awake rats by microdialysis with concentric dialysis probes and by chronoamperometry with electrochemical (stearate-graphite paste) recording electrodes, after inhibition of monoamine oxidase by pargyline and subsequent blockade of dopamine uptake by nomifensine. Pargyline (75 mg/kg, i.p.) increased dopamine overflow by 14 nM from a mean basal value of 9 nM as determined from dialysis probes implanted in the right striatum. Pargyline failed, however, to increase basal concentrations of dopamine measured by electrochemical electrodes implanted alone in the contralateral striatum. In contrast, 3 h following pargyline, administration of nomifensine (10 mg/kg, i.p.) increased extracellular dopamine concentrations to a similar magnitude above baseline levels in both right and left striata (135 and 127 nM, respectively). In a separate group of rats, electrochemical electrodes were implanted in the left striatum with the tip of the electrode placed directly adjacent to the lumen of a dialysis probe. In contrast to pargyline's inability to increase basal extracellular dopamine measured at individually implanted electrochemical electrodes in the striatum, pargyline administration increased dopamine concentrations measured at electrodes implanted adjacent to non-perfused dialysis probes to an extent similar to that observed by dialysis alone (25 vs 14 nM, respectively). The present study indicates that pargyline increases dopamine concentrations in the region of striatal tissue immediately adjacent to the shaft of a permanently implanted dialysis probe, but not at the tip of an electrochemical electrode. The former effect appears to reflect an interaction between monoamine oxidase inhibition and the effects elicited by the physical presence of the dialysis probe in tissue.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Reduction in glial fibrillary acidic protein mRNA abundance induced by (-)-deprenyl and other monoamine oxidase B inhibitors in C6 glioma cells.

Gliosis is commonly observed in the CNS following tissue damage, and it also occurs in aging and in many neurodegenerative diseases. Glial fibrillary acidic protein (GFAP) accumulation is a prominent feature of astrocytic gliosis. An inhibition or delay in GFAP synthesis could mitigate scar formation and thus reduce the formation of a physical barrier. The consequence of this would be to allow neurons and oligodendrocytes to reestablish a functional environment. (-)-Deprenyl, a specific monoamine oxidase (MAO) B inhibitor, has been used as an effective antiparkinsonian drug, and it has been reported to possess neuroprotective and neurorescue properties. Using northern and slot blots to detect GFAP mRNA in C6 glioma cells, we have demonstrated that (-)-deprenyl decreases the abundance of GFAP mRNA in a time- and dose-dependent manner. The effect seems to be specific to MAO B inhibitors because (+)-deprenyl and clorgyline exhibit no effect. This study indicates therefore that (-)-deprenyl may be useful for regulating astrogliosis following CNS injury as well as in some neurodegenerative diseases.

Animals↗
PubMed1986

Brain dialysis: in vivo metabolism of dopamine and serotonin by monoamine oxidase A but not B in the striatum of unrestrained rats.

A dialysis cannula was implanted into rat striatum while the animals were anesthetized, and the area was perfused with Ringer solution while the animals were unanesthetized after at least 3 days following surgery. Concentrations of the metabolites of 3,4-dihydroxyphenylethylamine (DA) and 5-hydroxytryptamine (5-HT) in the perfusate were determined by HPLC with electrochemical detection. Levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the perfusate significantly decreased after pargyline administration (50 mg/kg i.p.), which may inhibit not only monoamine oxidase (MAO)-B but also MAO-A in these high doses. The level of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) also decreased after pargyline treatment, although change in the relative level of 5-HIAA was less than that of DOPAC or HVA. To clarify the mechanisms for the metabolism of monoamines in rat striatum, highly specific MAO-A and -B inhibitors were used in the following experiments. Treatment with l-deprenyl (10 mg/kg), a specific inhibitor for MAO-B, did not cause any statistically significant change in DOPAC, HVA, and 5-HIAA levels. No significant change was found in rat striatal homogenates at 2 h after the same treatment with l-deprenyl. In contrast, low-dose treatment (1 mg/kg) with clorgyline, a specific inhibitor for MAO-A, caused a significant decrease in levels of these three metabolites in both the perfusates and tissue homogenates. In addition to the above three metabolites, the level of 3-methoxytyramine, which is an indicator of the amount of DA released, greatly increased after treatment with a low dose (1 mg/kg) of clorgyline.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Determination of the absolute concentrations of monoamine oxidase A and B in human tissues.

The concentrations of monoamine oxidase-A and -B were determined in homogenates of human cerebral cortex, caudatus and placenta and in human platelet-rich plasma and platelet membranes by determining the specific binding of tritium-labelled pargyline. The concentrations of the two enzyme forms were similar in both human brain regions examined. Determinations of the minimum quantities of clorgyline, (-)-deprenyl, J-508 or pargyline necessary to give complete inhibition of enzyme activity was found to give overestimates of the amounts of monoamine oxidase-A and -B present due to nonspecific binding of these inhibitors.

Autopsy↗
PubMed2006

Inhibition of monoamine oxidase B by analogues of the adenosine A2A receptor antagonist (E)-8-(3-chlorostyryl)caffeine (CSC).

The adenosine A2A receptor has emerged as a possible target for the treatment of Parkinson's disease (PD). Evidence suggests that antagonism of the A2A receptor not only improves the symptoms of the disease but may also protect against the underlying degenerative processes. We have recently reported that several known adenosine A2A receptor antagonists (A2A antagonists) also are moderate to very potent inhibitors of monoamine oxidase B (MAO-B). The most potent among these was (E)-8-(3-chlorostyryl)caffeine (CSC), a compound frequently used when examining the in vivo pharmacological effects of A2A antagonists. Since MAO-B inhibitors are also thought to possess antiparkinsonian properties, dual targeting drugs that block both MAO-B and A2A receptors may have enhanced therapeutic potential in the treatment of PD. In this study, we prepared selected analogues of CSC in an attempt to examine specific structural features that may be important for potent MAO-B inhibition. The results of a SAR study established that the potency of MAO-B inhibition by (E)-8-styrylcaffeinyl analogues depends upon the van der Waals volume (V(w)), lipophilicity (pi), and the Hammett constant (sigma(m)) of the substituents attached to C-3 of the phenyl ring of the styryl moiety. Potency also varies with substituents attached to C-4 with bulkiness (V(w)) and lipophilicity (pi) being the principal substituent descriptors.

Adenosine A2 Receptor Antagonists↗
PubMed1992

Brief transient ischemia induces long-term depletion of norepinephrine without affecting the aromatic amino acid decarboxylase and monoamine oxidase activities in the rat kidney.

Renal artery occlusion (RAO) for 30, 60 or 90 sec was found to reduce norepinephrine tissue levels in both the cortex and medulla of the rat, respectively, by 2 to 5%, 56 to 65% and 92 to 97%, but no significant change in dopamine tissue levels was found to occur. Similar effects were obtained with occlusion of the aorta proximally to the renal arteries for 90 sec. Administration of superoxide dismutase (40 mg/kg) immediately before RAO resulted in a marked protection of the norepinephrine depletion effect as caused by transient ischemia. The sodium-dependent formation of dopamine and 3,4-dihydroxyphenylacetic acid, the deaminated metabolite of dopamine, in renal slices loaded with L-3,4-dihydroxyphenylalanine (50 microM) was found to be similar in denervated and control kidneys. Type A and B monoamine oxidase activities were measured with the deamination of two specific substrates, respectively, [3H]-5-hydroxytryptamine and [14C]-beta-phenylethylamine, in homogenates of the renal cortex and renal medulla; neither type of monoamine oxidase, A or B, was found to be affected by denervation. The renal tissues collected for morphological observation were those in which RAO was performed for 90 sec. The general structure of the renal cortex was not affected by RAO, being similar in the control and the denervated kidney. In conclusion, the results presented suggest that the tissue damaging effect produced by RAO appears to be selective for the renal sympathetic innervation and seems to involve the generation of some reactive oxygen species, namely superoxide.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Strategy for the formation of parametric images under conditions of low injected radioactivity applied to PET studies with the irreversible monoamine oxidase A tracers [11C]clorgyline and deuterium-substituted [11C]clorgyline.

The construction of parametric positron emission tomography images of enzyme or receptor concentration obtained using irreversibly binding radiotracers presents problems not usually encountered with reversibly binding radiotracers. Difficulties are most apparent in brain regions having low blood flow and/or high enzyme or receptor concentration and are exacerbated with noisy data. This is especially true when minimal doses of radiotracer are administered. A comparison was recently reported of the irreversible monoamine oxidase A (MAO A) radiotracers [11C]clorgyline (CLG) and deuterium-substituted [11C]clorgyline (CLG-D) in the human brain using region of interest (ROI) analysis in which the authors observed an unexpected loss of image contrast with CLG-D compared with CLG. In order to more fully investigate patterns of binding of these irreversibly binding radiotracers, a strategy was devised to reduce noise in the generation of parametric images of the model term related to enzyme or receptor concentration. The generalized linear least squares (GLLS) method of Feng et al. (1995), a rapid linear method that is unbiased, was used for image-wide parameter estimation. Since GLLS can fail in the presence of large amounts of noise, local voxels were grouped within the image to increase the signal, and the GLLS method was combined with the standard nonlinear estimation methods when necessary. Voxels were grouped together depending on their proximity and whether they fell within a specified range of the time-integrated image. It was assumed that voxels meeting both criteria are functionally related. Simulations reflecting varying enzyme concentrations were performed to assess precision and accuracy of parameter estimates in the presence of varying amounts of noise. Using this approach, images were generated of the combination parameter lambdak3 (lambda = K1/k2, where K1 and k2 are plasma-to-tissue and tissue-to-plasma transport constants, respectively) that is related to enzyme concentration as well as images of the transport constant K1 for individual subjects. Reasonably high-quality images of both K1 and lambdak3 were obtained for CLG and CLG-D for individual subjects even with low injected doses averaging 6 mCi. While there were no differences in the K1 images, the lambdak3 images revealed the loss of contrast previously reported for CLG-D using the ROI analysis. This method should be generalizable to other tracers and should facilitate the analysis of group differences.

Brain↗
PubMedDate not supplied

[The role of monoamine oxidase in the regulation of mitochondrial energy functions].

Incubation of aldehyde dehydrogenase-free mitochondrial preparations with biogenic amines serotonin, tyramine, 2-phenylethylamine and 5-methoxytryptamine resulted in inhibition of enzymes activity of both outer (rotenone-insensitive NADH-cytochrome c reductase) and inner (succinate dehydrogenase, succinate cytochrome c reductase) mitochondrial membranes. Solubilization of mitochondria after the incubation did not influence the amine-induced alteration of succinate dehydrogenase activity. Pretreatment of the organelles with a mixture containing chlorgyline and deprenyl completely inhibited monoamine oxidase (MAO) activity and prevented the effects of all the amines studied on mitochondrial enzymes. MAO-dependent effects of 5-methoxytryptamine were fully reproduced by 5-methoxyindolyl-3-acetaldehyde (one of probable products of 5-methoxytryptamine deamination). The effect of the aldehyde was not prevented by chlorgyline and deprenyl. After selective inhibition of MAO-A by chlorgyline the order of MAO-B-dependent effects of biogenic amines on mitochondrial enzymes studied was as follows: tyramine greater than or equal to 2-phenylethylamine much greater than serotonin. In deprenyl pretreated mitochondria the potency of MAO-A-dependent effects of these amines was: serotonin greater than tyramine much greater than much greater than 2-phenylethylamine. The data obtained suggest that the product(s) of oxidative deamination of biogenic amines (probably the aldehydes) catalyzed by both types of MAO (MAO-A and MAO-B) are able to regulate the energy functions of mitochondria.

Animals↗
PubMed1987

Refractory depression treated with high doses of monoamine oxidase inhibitor.

Two treatment-refractory cases of depression were treated with doses of monoamine oxidase inhibitors (MAOIs) that exceeded the recommended therapeutic range. Both patients improved without any side effects. It appears that high doses of MAOIs when used with caution in responsible patients may be another method for treating refractory depression.

Adult↗
PubMed1996

Inhibition of monoamine oxidase B in the brains of smokers.

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.

Adult↗
PubMed1995

An allelic association study of monoamine oxidase B in Parkinson's disease.

A single-stranded conformational polymorphism in the monoamine oxidase B gene was shown to be A or G, 36 bases upstream from the intron 13-exon 14 boundary. An allelic association study revealed no statistically significant associations between this single-base polymorphism and Parkinson's disease, unlike the results of a previous study.

Adult↗
PubMed1990

Effect of monoamine oxidase inhibition on catecholamine levels: evidence for synthesis but not storage of epinephrine in rat spinal cord.

Epinephrine levels in the intermediolateral cell group in the rat spinal cord are very low, although there is a dense projection to this region from cells containing all the enzymes required for epinephrine biosynthesis. One explanation for this finding is that epinephrine in the nerve terminals is degraded as soon as it is synthesized, so that no epinephrine is actually stored in synaptic vesicles. To test this hypothesis, epinephrine levels were measured in spinal cord of rats pretreated with an inhibitor of monoamine oxidase, the major enzyme involved in epinephrine degradation. Selected other tissues (i.e. brainstem, hypothalamus, adrenal gland, superior cervical ganglion) were examined for comparison. Pargyline treatment (75 mg/kg i.p., 4 h prior to sacrifice) increased catecholamine levels in spinal cord, hypothalamus, and brainstem. However, the percent increase in epinephrine in the spinal cord and brainstem was much larger than that for dopamine and norepinephrine in the 3 central nervous system regions studied, as well as larger than that for epinephrine in the hypothalamus. These results suggest that phenylethanolamine N-methyltransferase (PNMT)-containing terminals in the rat spinal cord can synthesize epinephrine, but that little if any epinephrine is stored in synaptic vesicles due to the rapid metabolism of cytoplasmic catecholamines by monoamine oxidase. In contrast, pargyline pretreatment had no effect on catechol levels in the adrenal gland, suggesting that little metabolism of catecholamines takes place in those epinephrine-synthesizing cells. Furthermore, since pargyline pretreatment increased norepinephrine levels but decreased dopamine levels in the superior cervical ganglion, it is suggested that most of the dopamine in that sympathetic ganglion is present as a precursor to norepinephrine in noradrenergic postganglionic sympathetic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗