Greater Monoamine Oxidase A Binding in Alcohol Dependence

Matthews, Brittany A.; Kish, Stephen J.; Xu, Xin; Boileau, Isabelle; Rusjan, Pablo; Wilson, Alan A.; DiGiacomo, Daniel; Houle, Sylvain; Meyer, Jeffrey H.

doi:10.1016/j.biopsych.2013.10.010

Cited by 21 publications

(7 citation statements)

References 82 publications

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“…The ROIs were primarily defined using the Duvernoy (1999) atlas, with the exception of the divisions of the dorsal putamen and ventral striatum, which are described by Mawlawi et al (2001) . Details describing the delineation of each ROI have been previously described in the supplemental section of Matthews et al (2014) . The ROIs were delineated on the MRIs using a semi-automated method based on a template and nonlinear transformations ( Ashburner and Friston, 1997 , 1999 ; Rusjan et al, 2006 ).…”

Section: Methodsmentioning

confidence: 99%

Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors

Chiuccariello

Cooke

Miler

et al. 2015

IJNPPY

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Background:Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer’s, and Parkinson’s Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing.Methods:Major depressive episode (MDE) subjects underwent [11C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine.Results:Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300–600mg daily (n = 11), 83.75±5.52% for moclobemide at 900–1200mg daily (n = 9), and 86.82±6.89% for phenelzine at 45–60mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean ‘a’: 88.62±2.38%, mean ‘b’: 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45–60mg) and higher-dose moclobemide (900–1200mg) compared to lower-dose moclobemide [300–600mg; F(7,16) = 3.94, p = 0.01].Conclusions:These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300–600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets.

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Section: Methodsmentioning

confidence: 99%

Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors

Chiuccariello

Cooke

Miler

et al. 2015

IJNPPY

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“…Previous reports have shown that the KLF11 cell death pathway is upregulated in response to chronic ethanol exposure in rodents (Ou et al, 2011, 2014; Duncan et al, 2015; Nair et al, 2015), as well as in postmortem brain of AUD subjects (Udemgba et al, 2014). In addition, chronic ethanol-induced increases in both MAO-A and MAO-B expression and catalytic activity have been reported in rodents and humans (Rimondini et al, 2002; Ou et al, 2014; Matthews et al, 2014; Nair et al, 2015). The present study extended these observations on the KLF11-MAO pathway from the chronic ethanol model to acute, binge-like ethanol exposure.…”

Section: Discussionmentioning

confidence: 98%

Binge ethanol exposure increases the Krüppel-like factor 11-monoamine oxidase (MAO) pathway in rats: Examining the use of MAO inhibitors to prevent ethanol-induced brain injury

et al. 2016

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Binge drinking induces several neurotoxic consequences including oxidative stress and neurodegeneration. Because of these effects, drugs which prevent ethanol-induced damage to the brain may be clinically beneficial. In this study, we investigated the ethanol-mediated KLF11-MAO cell death cascade in the frontal cortex of Sprague–Dawley rats exposed to a modified Majchowicz 4-day binge ethanol model and control rats. Moreover, MAO inhibitors (MAOIs) were investigated for neuroprotective activity against binge ethanol. Binge ethanol-treated rats demonstrated a significant increase in KLF11, both MAO isoforms, protein oxidation and caspase-3, as well as a reduction in BDNF expression in the frontal cortex compared to control rats. MAOIs prevented these binge ethanol-induced changes, suggesting a neuroprotective benefit. Neither binge ethanol nor MAOI treatment significantly affected protein expression levels of the oxidative stress enzymes, SOD2 or catalase. Furthermore, ethanol-induced antinociception was enhanced following exposure to the 4-day ethanol binge. These results demonstrate that the KLF11-MAO pathway is activated by binge ethanol exposure and MAOIs are neuroprotective by preventing the binge ethanol-induced changes associated with this cell death cascade. This study supports KLF11-MAO as a mechanism of ethanol-induced neurotoxicity and cell death that could be targeted with MAOI drug therapy to alleviate alcohol-related brain injury. Further examination of MAOIs to reduce alcohol use disorder-related brain injury could provide pivotal insight to future pharmacotherapeutic opportunities.

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“…Additional regions sampled included subregions of the PFC (medial, ventrolateral, dorsolateral, and orbitofrontal), temporal cortex, parietal cortex, occipital cortex, thalamus, dorsal putamen, dorsal caudate, ventral striatum, and hippocampus. ROIs were defined as previously described 38 . ROIs were delineated on proton density magnetic resonance imaging scans (Signa 3-T MRI scanner, General Electric, Milwaukee, WI, USA; section thickness 2 mm, repetition time 6000 ms, echo time 8 ms, flip angle 90°, one excitation, acquisition matrix 256 × 192, and field of view 16.5 cm) using the in-house software, Regions of Mental Interest.…”

Section: Materials Participants and Methodsmentioning

confidence: 99%

A double-blind placebo-controlled trial of minocycline on translocator protein distribution volume in treatment-resistant major depressive disorder

et al. 2021

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Gliosis is implicated in the pathophysiology of many neuropsychiatric diseases, including treatment-resistant major depressive disorder (TRD). Translocator protein total distribution volume (TSPO VT), a brain marker mainly reflective of gliosis in disease, can be measured using positron emission tomography (PET). Minocycline reduces gliosis and translocator protein binding in rodents, but this is not established in humans. Here, the ability of oral minocycline to reduce TSPO VT was assessed in TRD. To determine whether oral minocycline, as compared to placebo, can reduce prefrontal cortex (PFC), anterior cingulate cortex (ACC), and insula TSPO VT in TRD, twenty-one TRD participants underwent two [18F]FEPPA PET scans to measure TSPO VT. These were completed before and after either oral minocycline 100 mg bid or placebo which was administered in a randomized double-blinded fashion for 8 weeks. There was no significant difference between the minocycline and placebo groups on change in TSPO VT within the PFC, ACC, and insula (repeated measures ANOVA, effect of group interaction, PFC: F1,19 = 0.28, P = 0.60; ACC: F1,19 = 0.54, P = 0.47; insula F1,19 = 1.6, P = 0.22). Oral minocycline had no significant effect on TSPO VT which suggests that this dosage is insufficient to reduce gliosis in TRD. To target gliosis in TRD either alternative therapeutics or intravenous formulations of minocycline should be investigated. These results also suggest that across neuropsychiatric diseases in humans, it should be assumed that oral minocycline will not reduce TSPO VT or gliosis unless empirically demonstrated.

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Greater Monoamine Oxidase A Binding in Alcohol Dependence

Cited by 21 publications

References 82 publications

Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors

Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors

Binge ethanol exposure increases the Krüppel-like factor 11-monoamine oxidase (MAO) pathway in rats: Examining the use of MAO inhibitors to prevent ethanol-induced brain injury

A double-blind placebo-controlled trial of minocycline on translocator protein distribution volume in treatment-resistant major depressive disorder

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