Cargando…
Glutamine antagonism attenuates physical and cognitive deficits in a model of MS
OBJECTIVE: To measure the impact of JHU-083, a novel prodrug of the glutamine antagonist 6-diazo-5-oxo-l-norleucine, on immune cell proliferation and activation, along with physical and cognitive impairments associated with the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHO...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745721/ https://www.ncbi.nlm.nih.gov/pubmed/31467038 http://dx.doi.org/10.1212/NXI.0000000000000609 |
_version_ | 1783451584891453440 |
---|---|
author | Hollinger, Kristen R. Smith, Matthew D. Kirby, Leslie A. Prchalova, Eva Alt, Jesse Rais, Rana Calabresi, Peter A. Slusher, Barbara S. |
author_facet | Hollinger, Kristen R. Smith, Matthew D. Kirby, Leslie A. Prchalova, Eva Alt, Jesse Rais, Rana Calabresi, Peter A. Slusher, Barbara S. |
author_sort | Hollinger, Kristen R. |
collection | PubMed |
description | OBJECTIVE: To measure the impact of JHU-083, a novel prodrug of the glutamine antagonist 6-diazo-5-oxo-l-norleucine, on immune cell proliferation and activation, along with physical and cognitive impairments associated with the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: Splenic-derived T cells and bone marrow–derived dendritic cells (DCs) were cultured, activated, and treated daily with vehicle or JHU-083. Proliferation and activation were measured via flow cytometry and IncuCyte live cell analysis. C57BL/6 mice were immunized for EAE. Vehicle or JHU-083 was administered orally every other day either from the time of immunization in the prevention paradigm or from the time of disease onset in the treatment paradigm. Disease scores and body weight were monitored. In the treatment paradigm, cognition was evaluated using the Barnes maze test. RESULTS: JHU-083 selectively inhibits T-cell proliferation and decreases T-cell activation, with no effect on DCs. In vivo, orally administered JHU-083 significantly decreases EAE severity in both prevention and treatment paradigms and reverses EAE-induced cognitive impairment. CONCLUSIONS: JHU-083, a well-tolerated, brain penetrable glutamine antagonist, is a promising novel treatment for both the physical and cognitive deficits of MS. |
format | Online Article Text |
id | pubmed-6745721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-67457212019-10-03 Glutamine antagonism attenuates physical and cognitive deficits in a model of MS Hollinger, Kristen R. Smith, Matthew D. Kirby, Leslie A. Prchalova, Eva Alt, Jesse Rais, Rana Calabresi, Peter A. Slusher, Barbara S. Neurol Neuroimmunol Neuroinflamm Article OBJECTIVE: To measure the impact of JHU-083, a novel prodrug of the glutamine antagonist 6-diazo-5-oxo-l-norleucine, on immune cell proliferation and activation, along with physical and cognitive impairments associated with the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: Splenic-derived T cells and bone marrow–derived dendritic cells (DCs) were cultured, activated, and treated daily with vehicle or JHU-083. Proliferation and activation were measured via flow cytometry and IncuCyte live cell analysis. C57BL/6 mice were immunized for EAE. Vehicle or JHU-083 was administered orally every other day either from the time of immunization in the prevention paradigm or from the time of disease onset in the treatment paradigm. Disease scores and body weight were monitored. In the treatment paradigm, cognition was evaluated using the Barnes maze test. RESULTS: JHU-083 selectively inhibits T-cell proliferation and decreases T-cell activation, with no effect on DCs. In vivo, orally administered JHU-083 significantly decreases EAE severity in both prevention and treatment paradigms and reverses EAE-induced cognitive impairment. CONCLUSIONS: JHU-083, a well-tolerated, brain penetrable glutamine antagonist, is a promising novel treatment for both the physical and cognitive deficits of MS. Lippincott Williams & Wilkins 2019-08-29 /pmc/articles/PMC6745721/ /pubmed/31467038 http://dx.doi.org/10.1212/NXI.0000000000000609 Text en Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (http://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Article Hollinger, Kristen R. Smith, Matthew D. Kirby, Leslie A. Prchalova, Eva Alt, Jesse Rais, Rana Calabresi, Peter A. Slusher, Barbara S. Glutamine antagonism attenuates physical and cognitive deficits in a model of MS |
title | Glutamine antagonism attenuates physical and cognitive deficits in a model of MS |
title_full | Glutamine antagonism attenuates physical and cognitive deficits in a model of MS |
title_fullStr | Glutamine antagonism attenuates physical and cognitive deficits in a model of MS |
title_full_unstemmed | Glutamine antagonism attenuates physical and cognitive deficits in a model of MS |
title_short | Glutamine antagonism attenuates physical and cognitive deficits in a model of MS |
title_sort | glutamine antagonism attenuates physical and cognitive deficits in a model of ms |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745721/ https://www.ncbi.nlm.nih.gov/pubmed/31467038 http://dx.doi.org/10.1212/NXI.0000000000000609 |
work_keys_str_mv | AT hollingerkristenr glutamineantagonismattenuatesphysicalandcognitivedeficitsinamodelofms AT smithmatthewd glutamineantagonismattenuatesphysicalandcognitivedeficitsinamodelofms AT kirbylesliea glutamineantagonismattenuatesphysicalandcognitivedeficitsinamodelofms AT prchalovaeva glutamineantagonismattenuatesphysicalandcognitivedeficitsinamodelofms AT altjesse glutamineantagonismattenuatesphysicalandcognitivedeficitsinamodelofms AT raisrana glutamineantagonismattenuatesphysicalandcognitivedeficitsinamodelofms AT calabresipetera glutamineantagonismattenuatesphysicalandcognitivedeficitsinamodelofms AT slusherbarbaras glutamineantagonismattenuatesphysicalandcognitivedeficitsinamodelofms |