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Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic pr...

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Autores principales: Nango, Hiroshi, Tsuruta, Komugi, Miyagishi, Hiroko, Aono, Yuri, Saigusa, Tadashi, Kosuge, Yasuhiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278279/
https://www.ncbi.nlm.nih.gov/pubmed/37337289
http://dx.doi.org/10.1186/s40035-023-00366-w
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author Nango, Hiroshi
Tsuruta, Komugi
Miyagishi, Hiroko
Aono, Yuri
Saigusa, Tadashi
Kosuge, Yasuhiro
author_facet Nango, Hiroshi
Tsuruta, Komugi
Miyagishi, Hiroko
Aono, Yuri
Saigusa, Tadashi
Kosuge, Yasuhiro
author_sort Nango, Hiroshi
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E(2) (PGE(2)) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE(2) levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE(2), but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE(2) in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE(2) biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE(2) induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE(2)-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE(2) in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.
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spelling pubmed-102782792023-06-20 Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis Nango, Hiroshi Tsuruta, Komugi Miyagishi, Hiroko Aono, Yuri Saigusa, Tadashi Kosuge, Yasuhiro Transl Neurodegener Review Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The pathogenesis of ALS remains largely unknown; however, inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS. Prostaglandin E(2) (PGE(2)) is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites. PGE(2) levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice. Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE(2), but the usefulness of this inhibitor has not yet been proven in clinical trials. In this review, we present current evidence on the involvement of PGE(2) in the progression of ALS and discuss the potential of microsomal prostaglandin E synthase (mPGES) and the prostaglandin receptor E-prostanoid (EP) 2 as therapeutic targets for ALS. Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system. In some situations, however, the receptors mediate neuroprotective effects. Our recent studies demonstrated that levels of mPGES-1, which catalyzes the final step of PGE(2) biosynthesis, are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1. In addition, in an experimental motor-neuron model used in studies of ALS, PGE(2) induces the production of reactive oxygen species and subsequent caspase-3-dependent cytotoxicity through activation of the EP2 receptor. Moreover, this PGE(2)-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice. Further understanding of the pathophysiological role of PGE(2) in neurodegeneration may provide new insights to guide the development of novel therapies for ALS. BioMed Central 2023-06-19 /pmc/articles/PMC10278279/ /pubmed/37337289 http://dx.doi.org/10.1186/s40035-023-00366-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Review
Nango, Hiroshi
Tsuruta, Komugi
Miyagishi, Hiroko
Aono, Yuri
Saigusa, Tadashi
Kosuge, Yasuhiro
Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis
title Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis
title_full Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis
title_fullStr Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis
title_full_unstemmed Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis
title_short Update on the pathological roles of prostaglandin E(2) in neurodegeneration in amyotrophic lateral sclerosis
title_sort update on the pathological roles of prostaglandin e(2) in neurodegeneration in amyotrophic lateral sclerosis
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10278279/
https://www.ncbi.nlm.nih.gov/pubmed/37337289
http://dx.doi.org/10.1186/s40035-023-00366-w
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