Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury

Abstract We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast)...

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Autores principales:	Aric F. Logsdon, Abigail G. Schindler, James S. Meabon, Mayumi Yagi, Melanie J. Herbert, William A. Banks, Murray A. Raskind, Desiree A. Marshall, C. Dirk Keene, Daniel P. Perl, Elaine R. Peskind, David G. Cook
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9e3fbcc0c8eb4496832f5b58a983b041
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spelling	oai:doaj.org-article:9e3fbcc0c8eb4496832f5b58a983b0412021-12-02T17:52:14ZNitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury10.1038/s41598-020-66113-72045-2322https://doaj.org/article/9e3fbcc0c8eb4496832f5b58a983b0412020-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-66113-7https://doaj.org/toc/2045-2322Abstract We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast) in cerebellum. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) administered after blast blocked BBB disruption and prevented CD4+ T-cell infiltration into cerebellum. L-NAME also blocked blast-induced increases in intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a critical role in regulating blood-to-brain immune cell trafficking. Blocking NOS-mediated BBB dysfunction during this acute/subacute post-blast interval (24–71 hours after the last blast) also prevented sensorimotor impairment on a rotarod task 30 days later, long after L-NAME cleared the body. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice. Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. These results also further implicate the cerebellum as a brain region vulnerable to blast-induced mTBI.Aric F. LogsdonAbigail G. SchindlerJames S. MeabonMayumi YagiMelanie J. HerbertWilliam A. BanksMurray A. RaskindDesiree A. MarshallC. Dirk KeeneDaniel P. PerlElaine R. PeskindDavid G. CookNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-14 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Aric F. Logsdon Abigail G. Schindler James S. Meabon Mayumi Yagi Melanie J. Herbert William A. Banks Murray A. Raskind Desiree A. Marshall C. Dirk Keene Daniel P. Perl Elaine R. Peskind David G. Cook Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury
description	Abstract We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast) in cerebellum. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) administered after blast blocked BBB disruption and prevented CD4+ T-cell infiltration into cerebellum. L-NAME also blocked blast-induced increases in intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a critical role in regulating blood-to-brain immune cell trafficking. Blocking NOS-mediated BBB dysfunction during this acute/subacute post-blast interval (24–71 hours after the last blast) also prevented sensorimotor impairment on a rotarod task 30 days later, long after L-NAME cleared the body. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice. Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. These results also further implicate the cerebellum as a brain region vulnerable to blast-induced mTBI.
format	article
author	Aric F. Logsdon Abigail G. Schindler James S. Meabon Mayumi Yagi Melanie J. Herbert William A. Banks Murray A. Raskind Desiree A. Marshall C. Dirk Keene Daniel P. Perl Elaine R. Peskind David G. Cook
author_facet	Aric F. Logsdon Abigail G. Schindler James S. Meabon Mayumi Yagi Melanie J. Herbert William A. Banks Murray A. Raskind Desiree A. Marshall C. Dirk Keene Daniel P. Perl Elaine R. Peskind David G. Cook
author_sort	Aric F. Logsdon
title	Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury
title_short	Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury
title_full	Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury
title_fullStr	Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury
title_full_unstemmed	Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury
title_sort	nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/9e3fbcc0c8eb4496832f5b58a983b041
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Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury

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