NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury

Abstract Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau pr...

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Autores principales:	Frances Corrigan, Ibolja Cernak, Kelly McAteer, Sarah C. Hellewell, Jeffrey V. Rosenfeld, Renée J. Turner, Robert Vink
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/17f3b7d7e2ed4471a869681cf7a6ab27
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spelling	oai:doaj.org-article:17f3b7d7e2ed4471a869681cf7a6ab272021-12-02T18:27:47ZNK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury10.1038/s41598-021-88237-02045-2322https://doaj.org/article/17f3b7d7e2ed4471a869681cf7a6ab272021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88237-0https://doaj.org/toc/2045-2322Abstract Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.Frances CorriganIbolja CernakKelly McAteerSarah C. HellewellJeffrey V. RosenfeldRenée J. TurnerRobert VinkNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Frances Corrigan Ibolja Cernak Kelly McAteer Sarah C. Hellewell Jeffrey V. Rosenfeld Renée J. Turner Robert Vink NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury
description	Abstract Exposure to repeated concussive traumatic brain injury (TBI) and to blast-induced TBI has been associated with the potential development of the neurodegenerative condition known as chronic traumatic encephalopathy (CTE). CTE is characterized by the accumulation of hyperphosphorylated tau protein, with the resultant tau tangles thought to initiate the cognitive and behavioral manifestations that appear as the condition progresses. However, the mechanisms linking concussive and blast TBI with tau hyperphosphorylation are unknown. Here we show that single moderate TBI, repeated concussive TBI and blast-induced mild TBI all result in hyperphosphorylation of tau via a substance P mediated mechanism. Post-injury administration of a substance P, NK1 receptor antagonist attenuated the injury-induced phosphorylation of tau by modulating the activity of several key kinases including Akt, ERK1/2 and JNK, and was associated with improvement in neurological outcome. We also demonstrate that inhibition of the TRPV1 mechanoreceptor, which is linked to substance P release, attenuated injury-associated tau hyperphosphorylation, but only when it was administered prior to injury. Our results demonstrate that TBI-mediated stimulation of brain mechanoreceptors is associated with substance P release and consequent tau hyperphosphorylation, with administration of an NK1 receptor antagonist attenuating tau phosphorylation and associated neurological deficits. NK1 antagonists may thus represent a pharmacological approach to attenuate the potential development of CTE following concussive and blast TBI.
format	article
author	Frances Corrigan Ibolja Cernak Kelly McAteer Sarah C. Hellewell Jeffrey V. Rosenfeld Renée J. Turner Robert Vink
author_facet	Frances Corrigan Ibolja Cernak Kelly McAteer Sarah C. Hellewell Jeffrey V. Rosenfeld Renée J. Turner Robert Vink
author_sort	Frances Corrigan
title	NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury
title_short	NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury
title_full	NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury
title_fullStr	NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury
title_full_unstemmed	NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury
title_sort	nk1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/17f3b7d7e2ed4471a869681cf7a6ab27
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NK1 antagonists attenuate tau phosphorylation after blast and repeated concussive injury

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