TrkB-enhancer facilitates functional recovery after traumatic brain injury

Abstract Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a p...

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Autores principales:	John Marshall, Joanna Szmydynger-Chodobska, Mengia S. Rioult-Pedotti, Kara Lau, Andrea T. Chin, Siva K. Reddy Kotla, Rakesh Kumar Tiwari, Keykavous Parang, Steven W. Threlkeld, Adam Chodobski
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/44c107a080a54523a1e0b98d597f1b43
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spelling	oai:doaj.org-article:44c107a080a54523a1e0b98d597f1b432021-12-02T15:06:09ZTrkB-enhancer facilitates functional recovery after traumatic brain injury10.1038/s41598-017-11316-82045-2322https://doaj.org/article/44c107a080a54523a1e0b98d597f1b432017-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-11316-8https://doaj.org/toc/2045-2322Abstract Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the post-traumatic activation of JNK in a rodent model of TBI. The recordings of field excitatory post-synaptic potentials in the hippocampal CA1 subfield demonstrate that TBI inhibits the expression of long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals, and that CN2097 attenuates this LTP impairment. Lastly, we demonstrate that CN2097 significantly improves the complex auditory processing deficits, which are impaired after injury. The multifunctionality of CN2097 strongly suggests that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma.John MarshallJoanna Szmydynger-ChodobskaMengia S. Rioult-PedottiKara LauAndrea T. ChinSiva K. Reddy KotlaRakesh Kumar TiwariKeykavous ParangSteven W. ThrelkeldAdam ChodobskiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q John Marshall Joanna Szmydynger-Chodobska Mengia S. Rioult-Pedotti Kara Lau Andrea T. Chin Siva K. Reddy Kotla Rakesh Kumar Tiwari Keykavous Parang Steven W. Threlkeld Adam Chodobski TrkB-enhancer facilitates functional recovery after traumatic brain injury
description	Abstract Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the post-traumatic activation of JNK in a rodent model of TBI. The recordings of field excitatory post-synaptic potentials in the hippocampal CA1 subfield demonstrate that TBI inhibits the expression of long-term potentiation (LTP) evoked by high-frequency stimulation of Schaffer collaterals, and that CN2097 attenuates this LTP impairment. Lastly, we demonstrate that CN2097 significantly improves the complex auditory processing deficits, which are impaired after injury. The multifunctionality of CN2097 strongly suggests that CN2097 could be highly efficacious in targeting complex secondary injury processes resulting from neurotrauma.
format	article
author	John Marshall Joanna Szmydynger-Chodobska Mengia S. Rioult-Pedotti Kara Lau Andrea T. Chin Siva K. Reddy Kotla Rakesh Kumar Tiwari Keykavous Parang Steven W. Threlkeld Adam Chodobski
author_facet	John Marshall Joanna Szmydynger-Chodobska Mengia S. Rioult-Pedotti Kara Lau Andrea T. Chin Siva K. Reddy Kotla Rakesh Kumar Tiwari Keykavous Parang Steven W. Threlkeld Adam Chodobski
author_sort	John Marshall
title	TrkB-enhancer facilitates functional recovery after traumatic brain injury
title_short	TrkB-enhancer facilitates functional recovery after traumatic brain injury
title_full	TrkB-enhancer facilitates functional recovery after traumatic brain injury
title_fullStr	TrkB-enhancer facilitates functional recovery after traumatic brain injury
title_full_unstemmed	TrkB-enhancer facilitates functional recovery after traumatic brain injury
title_sort	trkb-enhancer facilitates functional recovery after traumatic brain injury
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/44c107a080a54523a1e0b98d597f1b43
work_keys_str_mv	AT johnmarshall trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury AT joannaszmydyngerchodobska trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury AT mengiasrioultpedotti trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury AT karalau trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury AT andreatchin trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury AT sivakreddykotla trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury AT rakeshkumartiwari trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury AT keykavousparang trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury AT stevenwthrelkeld trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury AT adamchodobski trkbenhancerfacilitatesfunctionalrecoveryaftertraumaticbraininjury
_version_	1718388579041804288

TrkB-enhancer facilitates functional recovery after traumatic brain injury

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