The deamination of noradrenaline and 5-hydroxytryptamine by rat brain and heart monoamine oxidase and their inhibition by cimoxatone, toloxatone and MD 770222

Benedetti, Μ. Strolin; Boucher, Thierry; Fowler, Christopher J.

doi:10.1007/bf00512469

Cited by 38 publications

(5 citation statements)

References 29 publications

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“…Toloxatone, an antidepressant acting as a selective reversible inhibitor of MAO-A [20] revealed an IC 50 value of 6.71 μM ( Figure 4C, Table 1). [19,23] Increased and altered levels of monoamines are sometimes produced as a result of MAO inhibition and it was therefore of interest to determine how 5-IT compared with other inhibitors as summarized in Table 1. The fact that moclobemide is considered a good inhibitor of MAO-A in-vivo suggested that this might correspond to the formation of an active metabolite.…”

Section: Resultsmentioning

confidence: 99%

“…Results obtained for harmaline and toloxatone were also in good agreement with previous reports. [19,23] Increased and altered levels of monoamines are sometimes produced as a result of MAO inhibition and it was therefore of interest to determine how 5-IT compared with other inhibitors as summarized in Table 1. 5-IT was a relatively potent inhibitor of human MAO-A but it was found to be at least ten times less potent than the irreversible MAO-A inhibitor clorgyline (K i 0.25 μM vs. 0.016 μM).…”

Section: Resultsmentioning

confidence: 99%

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5‐(2‐Aminopropyl)indole (5‐IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO)

Herraiz

Brandt

2013

Drug Testing and Analysis

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5-(2-Aminopropyl)indole (5-IT) is a psychoactive compound that has recently been associated with several fatal and non-fatal intoxications in a number of European countries. There are indications that acute effects may include symptoms of monoaminergic (e.g. serotonin) toxicity and one mechanism involved in the increase of serotonin levels includes the inhibition of monoamine oxidase. This study investigated the effect of 5-IT on human MAO-A and -B isozymes using kynuramine as the substrate. Substrate conversion to 4-hydroxyquinoline was monitored by high-performance liquid chromatography coupled to diode array detection. This method was employed to determine the extent of MAO inhibition (IC50 and Ki ) and it was found that 5-IT was a selective, competitive and reversible inhibitor of MAO-A. 5-IT revealed a relatively potent ability to inhibit MAO-A (IC50 =1.6 μM and Ki =0.25 μM) while MAO-B inhibition was not observed (0-500 μM 5-IT). Under identical experimental conditions, other established inhibitors of MAO-A and antidepressants provided the following IC50 values: clorgyline 16 nM, harmaline 20 nM, toloxatone 6.7 μM and moclobemide >500 μM. These data indicated that 5-IT was less potent than clorgyline and harmaline but more potent than toloxatone and moclobemide under the in-vitro conditions studied. The inhibition of MAO-A suggests that 5-IT by itself or in combination with other substances may be able to potentiate serotonergic/monoaminergic effects and further studies are needed to clarify its relevance to the adverse effects reported for 5-IT.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

5‐(2‐Aminopropyl)indole (5‐IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO)

Herraiz

Brandt

2013

Drug Testing and Analysis

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“…Of note, NE levels were significantly higher than those observed in WT mice in both regions (although the amygdalar content of this monoamine was still significantly lower than its MAO-A KO counterpart). The impact of small amounts of MAO-A on NE is likely more limited than that on 5-HT, in view of the much lower affinity (Strolin Benedetti et al, 1983), as well as the important role of catecholamine-O-methyl-transferase in NE degradation.…”

Section: Discussionmentioning

confidence: 97%

Social Deficits and Perseverative Behaviors, but not Overt Aggression, in MAO-A Hypomorphic Mice

Bortolato¹,

Chen²,

Godar³

et al. 2011

Neuropsychopharmacol

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Monoamine oxidase (MAO)-A is a key enzyme for the degradation of brain serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE). In humans and mice, total MAO-A deficiency results in high 5-HT and NE levels, as well as elevated reactive aggression. Here we report the generation of MAO-A(Neo) mice, a novel line of hypomorphic MAO-A mutants featuring the insertion of a floxed neomycin-resistance cassette in intron-12 of the Maoa gene. This construct resulted in a chimeric, non-functional variant of the Maoa-Neo transcript, with a truncated C-terminus, likely due to aberrant splicing; these deficits notwithstanding, small amounts of functional Maoa transcript were found in the brain of MAO-A(Neo) mice. In the prefrontal cortex and amygdala, MAO-A(Neo) mice showed low, yet detectable, MAO-A catalytic activity, as well as 5-HT levels equivalent to WT littermates; conversely, the hippocampus and midbrain of MAO-A(Neo) mice featured a neurochemical profile akin to MAO-A-knockout (KO) mice, with undetectable MAO-A activity and high 5-HT concentrations. MAO-A(Neo) mice showed significant increases in dendritic length in the pyramidal neurons of orbitofrontal cortex, but not basolateral amygdala, in comparison with WT littermates; by contrast, the orbitofrontal cortex of MAO-A KO mice showed significant reductions in basilar dendritic length, as well as a profound increase in apical dendritic length. MAO-A(Neo) mice showed a unique set of behavioral abnormalities, encompassing reduced open-field locomotion, perseverative responses, such as marble burying and water mist-induced grooming, and a lack of anxiety-like behaviors in the elevated plus-maze and light-dark box paradigms. Notably, whereas MAO-A(Neo) and KO mice showed significant reductions in social interaction, only the latter genotype showed increases in resident-intruder aggression. Taken together, our findings indicate that MAO A hypomorphism results in behavioral and morphological alterations distinct from those featured by MAO-A KO mice.

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“…In the rat heart, MAO-A is responsible for the metabolism of norepinephrine, 5-OH tryptamine and also [3-phenethylamine; this last substrate is usually oxidized by MAO-B (e.g. in brain and liver) (57). Amines such as norepinephrine are important in regulation of myocardial work as neurotransmitter of the orthosympathetic.…”

Section: Conditions (At + Methanol)mentioning

confidence: 99%

Myocardial H2O2 production in the unanaesthetized rat Influence of fasting, myocardial load and inhibition of superoxide dismutase and monoamine oxidase

Kerckaert

Roels

1986

Basic Res Cardiol

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Myocardial H2O2 production was studied by means of the in vivo administration of aminotriazole (AT), which inactivates the catalase-H2O2 complex compound I. Measurements of the residual catalase activity in male and female rats indicate that beta-oxidation of fatty acids in peroxisomes does not contribute in a substantial way to energy production in response to fasting or to an increased myocardial load, despite previous data on peroxisomes in myocardium. Superoxide dismutase (SOD) inhibition by diethyldithiocarbamate demonstrates that SOD participates in the production of H2O2 in physiological conditions. Such a role was not demonstrated for monoamine oxidase through inhibition by phenelzine.

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The deamination of noradrenaline and 5-hydroxytryptamine by rat brain and heart monoamine oxidase and their inhibition by cimoxatone, toloxatone and MD 770222

Cited by 38 publications

References 29 publications

5‐(2‐Aminopropyl)indole (5‐IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO)

5‐(2‐Aminopropyl)indole (5‐IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO)

Social Deficits and Perseverative Behaviors, but not Overt Aggression, in MAO-A Hypomorphic Mice

Myocardial H2O2 production in the unanaesthetized rat Influence of fasting, myocardial load and inhibition of superoxide dismutase and monoamine oxidase

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