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Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS). Although classically considered a demyelinating disease, neuroaxonal injury occurs in both the acute and chronic phases and represents a pathologic substrate of disability not targeted by current therapies. N...

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Autores principales: Godfrey, Wesley H., Hwang, Soonmyung, Cho, Kaho, Shanmukha, Shruthi, Gharibani, Payam, Abramson, Efrat, Kornberg, Michael Davin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9902867/
https://www.ncbi.nlm.nih.gov/pubmed/36761918
http://dx.doi.org/10.3389/fneur.2022.979659
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author Godfrey, Wesley H.
Hwang, Soonmyung
Cho, Kaho
Shanmukha, Shruthi
Gharibani, Payam
Abramson, Efrat
Kornberg, Michael Davin
author_facet Godfrey, Wesley H.
Hwang, Soonmyung
Cho, Kaho
Shanmukha, Shruthi
Gharibani, Payam
Abramson, Efrat
Kornberg, Michael Davin
author_sort Godfrey, Wesley H.
collection PubMed
description Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS). Although classically considered a demyelinating disease, neuroaxonal injury occurs in both the acute and chronic phases and represents a pathologic substrate of disability not targeted by current therapies. Nitric oxide (NO) generated by CNS macrophages and microglia contributes to neuroaxonal injury in all phases of MS, but candidate therapies that prevent NO-mediated injury have not been identified. Here, we demonstrate that the multifunctional protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is robustly nitrosylated in the CNS in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. GAPDH nitrosylation is blocked in vivo with daily administration of CGP3466b, a CNS-penetrant compound with an established safety profile in humans. Consistent with the known role of nitrosylated GAPDH (SNO-GAPDH) in neuronal cell death, blockade of SNO-GAPDH with CGP3466b attenuates neurologic disability and reduces axonal injury in EAE independent of effects on the immune system. Our findings suggest that SNO-GAPDH contributes to neuroaxonal injury during neuroinflammation and identify CGP3466b as a candidate neuroprotective therapy in MS.
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spelling pubmed-99028672023-02-08 Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis Godfrey, Wesley H. Hwang, Soonmyung Cho, Kaho Shanmukha, Shruthi Gharibani, Payam Abramson, Efrat Kornberg, Michael Davin Front Neurol Neurology Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS). Although classically considered a demyelinating disease, neuroaxonal injury occurs in both the acute and chronic phases and represents a pathologic substrate of disability not targeted by current therapies. Nitric oxide (NO) generated by CNS macrophages and microglia contributes to neuroaxonal injury in all phases of MS, but candidate therapies that prevent NO-mediated injury have not been identified. Here, we demonstrate that the multifunctional protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is robustly nitrosylated in the CNS in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. GAPDH nitrosylation is blocked in vivo with daily administration of CGP3466b, a CNS-penetrant compound with an established safety profile in humans. Consistent with the known role of nitrosylated GAPDH (SNO-GAPDH) in neuronal cell death, blockade of SNO-GAPDH with CGP3466b attenuates neurologic disability and reduces axonal injury in EAE independent of effects on the immune system. Our findings suggest that SNO-GAPDH contributes to neuroaxonal injury during neuroinflammation and identify CGP3466b as a candidate neuroprotective therapy in MS. Frontiers Media S.A. 2023-01-24 /pmc/articles/PMC9902867/ /pubmed/36761918 http://dx.doi.org/10.3389/fneur.2022.979659 Text en Copyright © 2023 Godfrey, Hwang, Cho, Shanmukha, Gharibani, Abramson and Kornberg. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Godfrey, Wesley H.
Hwang, Soonmyung
Cho, Kaho
Shanmukha, Shruthi
Gharibani, Payam
Abramson, Efrat
Kornberg, Michael Davin
Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis
title Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis
title_full Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis
title_fullStr Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis
title_full_unstemmed Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis
title_short Therapeutic potential of blocking GAPDH nitrosylation with CGP3466b in experimental autoimmune encephalomyelitis
title_sort therapeutic potential of blocking gapdh nitrosylation with cgp3466b in experimental autoimmune encephalomyelitis
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9902867/
https://www.ncbi.nlm.nih.gov/pubmed/36761918
http://dx.doi.org/10.3389/fneur.2022.979659
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