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Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice

Neuropsychological deficits, including impairments in learning and memory, occur after spinal cord injury (SCI). In experimental SCI models, we and others have reported that such changes reflect sustained microglia activation in the brain that is associated with progressive neurodegeneration. In the...

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Autores principales: Li, Yun, Ritzel, Rodney M., Khan, Niaz, Cao, Tuoxin, He, Junyun, Lei, Zhuofan, Matyas, Jessica J., Sabirzhanov, Boris, Liu, Simon, Li, Hui, Stoica, Bogdan A., Loane, David J., Faden, Alan I., Wu, Junfang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545988/
https://www.ncbi.nlm.nih.gov/pubmed/33052221
http://dx.doi.org/10.7150/thno.49199
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author Li, Yun
Ritzel, Rodney M.
Khan, Niaz
Cao, Tuoxin
He, Junyun
Lei, Zhuofan
Matyas, Jessica J.
Sabirzhanov, Boris
Liu, Simon
Li, Hui
Stoica, Bogdan A.
Loane, David J.
Faden, Alan I.
Wu, Junfang
author_facet Li, Yun
Ritzel, Rodney M.
Khan, Niaz
Cao, Tuoxin
He, Junyun
Lei, Zhuofan
Matyas, Jessica J.
Sabirzhanov, Boris
Liu, Simon
Li, Hui
Stoica, Bogdan A.
Loane, David J.
Faden, Alan I.
Wu, Junfang
author_sort Li, Yun
collection PubMed
description Neuropsychological deficits, including impairments in learning and memory, occur after spinal cord injury (SCI). In experimental SCI models, we and others have reported that such changes reflect sustained microglia activation in the brain that is associated with progressive neurodegeneration. In the present study, we examined the effect of pharmacological depletion of microglia on posttraumatic cognition, depressive-like behavior, and brain pathology after SCI in mice. Methods: Young adult male C57BL/6 mice were subjected to moderate/severe thoracic spinal cord contusion. Microglial depletion was induced with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 administered starting either 3 weeks before injury or one day post-injury and continuing through 6 weeks after SCI. Neuroinflammation in the injured spinal cord and brain was assessed using flow cytometry and NanoString technology. Neurological function was evaluated using a battery of neurobehavioral tests including motor function, cognition, and depression. Lesion volume and neuronal counts were quantified by unbiased stereology. Results: Flow cytometry analysis demonstrated that PLX5622 pre-treatment significantly reduced the number of microglia, as well as infiltrating monocytes and neutrophils, and decreased reactive oxygen species production in these cells from injured spinal cord at 2-days post-injury. Post-injury PLX5622 treatment reduced both CD45(int) microglia and CD45(hi) myeloid counts at 7-days. Following six weeks of PLX5622 treatment, there were substantial changes in the spinal cord and brain transcriptomes, including those involved in neuroinflammation. These alterations were associated with improved neuronal survival in the brain and neurological recovery. Conclusion: These findings indicate that pharmacological microglia-deletion reduces neuroinflammation in the injured spinal cord and brain, improving recovery of cognition, depressive-like behavior, and motor function.
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spelling pubmed-75459882020-10-12 Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice Li, Yun Ritzel, Rodney M. Khan, Niaz Cao, Tuoxin He, Junyun Lei, Zhuofan Matyas, Jessica J. Sabirzhanov, Boris Liu, Simon Li, Hui Stoica, Bogdan A. Loane, David J. Faden, Alan I. Wu, Junfang Theranostics Research Paper Neuropsychological deficits, including impairments in learning and memory, occur after spinal cord injury (SCI). In experimental SCI models, we and others have reported that such changes reflect sustained microglia activation in the brain that is associated with progressive neurodegeneration. In the present study, we examined the effect of pharmacological depletion of microglia on posttraumatic cognition, depressive-like behavior, and brain pathology after SCI in mice. Methods: Young adult male C57BL/6 mice were subjected to moderate/severe thoracic spinal cord contusion. Microglial depletion was induced with the colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 administered starting either 3 weeks before injury or one day post-injury and continuing through 6 weeks after SCI. Neuroinflammation in the injured spinal cord and brain was assessed using flow cytometry and NanoString technology. Neurological function was evaluated using a battery of neurobehavioral tests including motor function, cognition, and depression. Lesion volume and neuronal counts were quantified by unbiased stereology. Results: Flow cytometry analysis demonstrated that PLX5622 pre-treatment significantly reduced the number of microglia, as well as infiltrating monocytes and neutrophils, and decreased reactive oxygen species production in these cells from injured spinal cord at 2-days post-injury. Post-injury PLX5622 treatment reduced both CD45(int) microglia and CD45(hi) myeloid counts at 7-days. Following six weeks of PLX5622 treatment, there were substantial changes in the spinal cord and brain transcriptomes, including those involved in neuroinflammation. These alterations were associated with improved neuronal survival in the brain and neurological recovery. Conclusion: These findings indicate that pharmacological microglia-deletion reduces neuroinflammation in the injured spinal cord and brain, improving recovery of cognition, depressive-like behavior, and motor function. Ivyspring International Publisher 2020-09-14 /pmc/articles/PMC7545988/ /pubmed/33052221 http://dx.doi.org/10.7150/thno.49199 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Li, Yun
Ritzel, Rodney M.
Khan, Niaz
Cao, Tuoxin
He, Junyun
Lei, Zhuofan
Matyas, Jessica J.
Sabirzhanov, Boris
Liu, Simon
Li, Hui
Stoica, Bogdan A.
Loane, David J.
Faden, Alan I.
Wu, Junfang
Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice
title Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice
title_full Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice
title_fullStr Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice
title_full_unstemmed Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice
title_short Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice
title_sort delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545988/
https://www.ncbi.nlm.nih.gov/pubmed/33052221
http://dx.doi.org/10.7150/thno.49199
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