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Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline
PURPOSE: In Alzheimer’s disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminerg...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5281649/ https://www.ncbi.nlm.nih.gov/pubmed/27633250 http://dx.doi.org/10.1007/s00259-016-3510-6 |
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author | Sturm, Stefan Forsberg, Anton Nave, Stephane Stenkrona, Per Seneca, Nicholas Varrone, Andrea Comley, Robert A. Fazio, Patrik Jamois, Candice Nakao, Ryuji Ejduk, Zbigniew Al-Tawil, Nabil Akenine, Ulrika Halldin, Christer Andreasen, Niels Ricci, Benedicte |
author_facet | Sturm, Stefan Forsberg, Anton Nave, Stephane Stenkrona, Per Seneca, Nicholas Varrone, Andrea Comley, Robert A. Fazio, Patrik Jamois, Candice Nakao, Ryuji Ejduk, Zbigniew Al-Tawil, Nabil Akenine, Ulrika Halldin, Christer Andreasen, Niels Ricci, Benedicte |
author_sort | Sturm, Stefan |
collection | PubMed |
description | PURPOSE: In Alzheimer’s disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577 and EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD. METHODS: This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [(11)C]-(L)-deprenyl-D(2) radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6–15 days. RESULTS: At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an E(max) of ∼80–90 % across brain regions of interest and in an EC(50) of 1–2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition. CONCLUSIONS: This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00259-016-3510-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5281649 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-52816492017-02-13 Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline Sturm, Stefan Forsberg, Anton Nave, Stephane Stenkrona, Per Seneca, Nicholas Varrone, Andrea Comley, Robert A. Fazio, Patrik Jamois, Candice Nakao, Ryuji Ejduk, Zbigniew Al-Tawil, Nabil Akenine, Ulrika Halldin, Christer Andreasen, Niels Ricci, Benedicte Eur J Nucl Med Mol Imaging Original Article PURPOSE: In Alzheimer’s disease (AD), increased metabolism of monoamines by monoamine oxidase type B (MAO-B) leads to the production of toxic reactive oxygen species (ROS), which are thought to contribute to disease pathogenesis. Inhibition of the MAO-B enzyme may restore brain levels of monoaminergic neurotransmitters, reduce the formation of toxic ROS and reduce neuroinflammation (reactive astrocytosis), potentially leading to neuroprotection. Sembragiline (also referred as RO4602522, RG1577 and EVT 302 in previous communications) is a potent, selective and reversible inhibitor of MAO-B developed as a potential treatment for AD. METHODS: This study assessed the relationship between plasma concentration of sembragiline and brain MAO-B inhibition in patients with AD and in healthy elderly control (EC) subjects. Positron emission tomography (PET) scans using [(11)C]-(L)-deprenyl-D(2) radiotracer were performed in ten patients with AD and six EC subjects, who received sembragiline each day for 6–15 days. RESULTS: At steady state, the relationship between sembragiline plasma concentration and MAO-B inhibition resulted in an E(max) of ∼80–90 % across brain regions of interest and in an EC(50) of 1–2 ng/mL. Data in patients with AD and EC subjects showed that near-maximal inhibition of brain MAO-B was achieved with 1 mg sembragiline daily, regardless of the population, whereas lower doses resulted in lower and variable brain MAO-B inhibition. CONCLUSIONS: This PET study confirmed that daily treatment of at least 1 mg sembragiline resulted in near-maximal inhibition of brain MAO-B enzyme in patients with AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00259-016-3510-6) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-09-16 2017 /pmc/articles/PMC5281649/ /pubmed/27633250 http://dx.doi.org/10.1007/s00259-016-3510-6 Text en © The Author(s) 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Article Sturm, Stefan Forsberg, Anton Nave, Stephane Stenkrona, Per Seneca, Nicholas Varrone, Andrea Comley, Robert A. Fazio, Patrik Jamois, Candice Nakao, Ryuji Ejduk, Zbigniew Al-Tawil, Nabil Akenine, Ulrika Halldin, Christer Andreasen, Niels Ricci, Benedicte Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline |
title | Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline |
title_full | Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline |
title_fullStr | Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline |
title_full_unstemmed | Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline |
title_short | Positron emission tomography measurement of brain MAO-B inhibition in patients with Alzheimer’s disease and elderly controls after oral administration of sembragiline |
title_sort | positron emission tomography measurement of brain mao-b inhibition in patients with alzheimer’s disease and elderly controls after oral administration of sembragiline |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5281649/ https://www.ncbi.nlm.nih.gov/pubmed/27633250 http://dx.doi.org/10.1007/s00259-016-3510-6 |
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