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Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration. There are no cures or effective treatments for ALS. Therapeutic hypothermia is effectively used clinically to mitigate mortality in patients with acute acquired brain injury and in surgica...

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Autores principales: Martin, Lee J., Niedzwiecki, Mark V., Wong, Margaret
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913914/
https://www.ncbi.nlm.nih.gov/pubmed/33557211
http://dx.doi.org/10.3390/cells10020320
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author Martin, Lee J.
Niedzwiecki, Mark V.
Wong, Margaret
author_facet Martin, Lee J.
Niedzwiecki, Mark V.
Wong, Margaret
author_sort Martin, Lee J.
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration. There are no cures or effective treatments for ALS. Therapeutic hypothermia is effectively used clinically to mitigate mortality in patients with acute acquired brain injury and in surgical settings to minimize secondary brain injury. The efficacy of therapeutic hypothermia in chronic neurodegenerative disorders has not been examined. We tested the hypothesis that mild hypothermia/cold acclimation is therapeutic in a transgenic mouse model of ALS caused by expression of mutated human superoxide dismutase-1 gene. At presymptomatic stages of disease, body temperatures (oral and axial) of mutant male mice were persistently hyperthermic (38–38.5 °C) compared to littermate controls, but at end-stage disease mice were generally hypothermic (36–36.5 °C). Presymptomatic mutant mice (awake-freely moving) were acclimated to systemic mild hypothermia using an environmentally controlled chamber (12 h-on/12-off or 24 h-on/24 h-off) to lower body temperature (1–3 °C). Cooled ALS mice showed a significant delay in disease onset (103–112 days) compared to normothermia mice (80–90 days) and exhibited significant attenuation of functional decline in motor performance. Cooled mice examined at 80 days had reduced motor neuron loss, mitochondrial swelling, and spinal cord inflammation compared to non-cooled mice. Cooling attenuated the loss of heat-shock protein 70, mitochondrial uncoupling protein-3, and sumoylated-1 (SUMO1)-conjugated proteins in skeletal muscle and disengaged the mitochondrial permeability transition pore. Cooled ALS mice had a significant extension of lifespan (148 ± 7 days) compared to normothermic mice (135 ± 4 days). Thus, intermittent systemic mild hypothermia is therapeutic in mouse ALS with protective effects manifested within the CNS and skeletal muscle that target mitochondria.
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spelling pubmed-79139142021-02-28 Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS Martin, Lee J. Niedzwiecki, Mark V. Wong, Margaret Cells Article Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes motor neuron degeneration. There are no cures or effective treatments for ALS. Therapeutic hypothermia is effectively used clinically to mitigate mortality in patients with acute acquired brain injury and in surgical settings to minimize secondary brain injury. The efficacy of therapeutic hypothermia in chronic neurodegenerative disorders has not been examined. We tested the hypothesis that mild hypothermia/cold acclimation is therapeutic in a transgenic mouse model of ALS caused by expression of mutated human superoxide dismutase-1 gene. At presymptomatic stages of disease, body temperatures (oral and axial) of mutant male mice were persistently hyperthermic (38–38.5 °C) compared to littermate controls, but at end-stage disease mice were generally hypothermic (36–36.5 °C). Presymptomatic mutant mice (awake-freely moving) were acclimated to systemic mild hypothermia using an environmentally controlled chamber (12 h-on/12-off or 24 h-on/24 h-off) to lower body temperature (1–3 °C). Cooled ALS mice showed a significant delay in disease onset (103–112 days) compared to normothermia mice (80–90 days) and exhibited significant attenuation of functional decline in motor performance. Cooled mice examined at 80 days had reduced motor neuron loss, mitochondrial swelling, and spinal cord inflammation compared to non-cooled mice. Cooling attenuated the loss of heat-shock protein 70, mitochondrial uncoupling protein-3, and sumoylated-1 (SUMO1)-conjugated proteins in skeletal muscle and disengaged the mitochondrial permeability transition pore. Cooled ALS mice had a significant extension of lifespan (148 ± 7 days) compared to normothermic mice (135 ± 4 days). Thus, intermittent systemic mild hypothermia is therapeutic in mouse ALS with protective effects manifested within the CNS and skeletal muscle that target mitochondria. MDPI 2021-02-04 /pmc/articles/PMC7913914/ /pubmed/33557211 http://dx.doi.org/10.3390/cells10020320 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Martin, Lee J.
Niedzwiecki, Mark V.
Wong, Margaret
Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS
title Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS
title_full Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS
title_fullStr Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS
title_full_unstemmed Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS
title_short Chronic Intermittent Mild Whole-Body Hypothermia Is Therapeutic in a Mouse Model of ALS
title_sort chronic intermittent mild whole-body hypothermia is therapeutic in a mouse model of als
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913914/
https://www.ncbi.nlm.nih.gov/pubmed/33557211
http://dx.doi.org/10.3390/cells10020320
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