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Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury
While calpains have long been implicated in neurodegeneration, no calpain inhibitor has been developed for the treatment of neurodegeneration. This is partly due to the lack of understanding of the specific functions of most of the 15 members of the calpain family. Work from our laboratory over the...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10684478/ https://www.ncbi.nlm.nih.gov/pubmed/37474874 http://dx.doi.org/10.1007/s13311-023-01407-y |
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author | Baudry, Michel Luo, Yun Lyna Bi, Xiaoning |
author_facet | Baudry, Michel Luo, Yun Lyna Bi, Xiaoning |
author_sort | Baudry, Michel |
collection | PubMed |
description | While calpains have long been implicated in neurodegeneration, no calpain inhibitor has been developed for the treatment of neurodegeneration. This is partly due to the lack of understanding of the specific functions of most of the 15 members of the calpain family. Work from our laboratory over the last 5–10 years has revealed that calpain-1 and calpain-2, two of the major calpain isoforms in the brain, play opposite roles in both synaptic plasticity/learning and memory and neuroprotection/neurodegeneration. Thus, calpain-1 activation is required for triggering certain forms of synaptic plasticity and for learning some types of information and is neuroprotective. In contrast, calpain-2 activation limits the extent of synaptic plasticity and of learning and is neurodegenerative. These results have been validated with the use of calpain-1 knock-out mice and mice with a selective calpain-2 deletion in excitatory neurons of the forebrain. Through a medicinal chemistry campaign, we have identified a number of selective calpain-2 inhibitors and shown that these inhibitors do facilitate learning of certain tasks and are neuroprotective in a number of animal models of acute neurodegeneration. One of these inhibitors, NA-184, is currently being developed for the treatment of traumatic brain injury, and clinical trials are being planned. |
format | Online Article Text |
id | pubmed-10684478 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-106844782023-11-30 Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury Baudry, Michel Luo, Yun Lyna Bi, Xiaoning Neurotherapeutics Review While calpains have long been implicated in neurodegeneration, no calpain inhibitor has been developed for the treatment of neurodegeneration. This is partly due to the lack of understanding of the specific functions of most of the 15 members of the calpain family. Work from our laboratory over the last 5–10 years has revealed that calpain-1 and calpain-2, two of the major calpain isoforms in the brain, play opposite roles in both synaptic plasticity/learning and memory and neuroprotection/neurodegeneration. Thus, calpain-1 activation is required for triggering certain forms of synaptic plasticity and for learning some types of information and is neuroprotective. In contrast, calpain-2 activation limits the extent of synaptic plasticity and of learning and is neurodegenerative. These results have been validated with the use of calpain-1 knock-out mice and mice with a selective calpain-2 deletion in excitatory neurons of the forebrain. Through a medicinal chemistry campaign, we have identified a number of selective calpain-2 inhibitors and shown that these inhibitors do facilitate learning of certain tasks and are neuroprotective in a number of animal models of acute neurodegeneration. One of these inhibitors, NA-184, is currently being developed for the treatment of traumatic brain injury, and clinical trials are being planned. Springer International Publishing 2023-07-20 2023-10 /pmc/articles/PMC10684478/ /pubmed/37474874 http://dx.doi.org/10.1007/s13311-023-01407-y 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/) . |
spellingShingle | Review Baudry, Michel Luo, Yun Lyna Bi, Xiaoning Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury |
title | Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury |
title_full | Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury |
title_fullStr | Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury |
title_full_unstemmed | Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury |
title_short | Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury |
title_sort | calpain-2 inhibitors as therapy for traumatic brain injury |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10684478/ https://www.ncbi.nlm.nih.gov/pubmed/37474874 http://dx.doi.org/10.1007/s13311-023-01407-y |
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