P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury

Terry C Yin; Jeremiah K Britt; Héctor De Jesús-Cortés; Yuan Lu; Rachel M Genova; Michael Z Khan; Jaymie R Voorhees; Jianqiang Shao; Aaron C Katzman; Paula J Huntington; Cassie Wassink; Latisha McDaniel; Elizabeth A Newell; Laura M Dutca; Jacinth Naidoo; Huxing Cui; Alexander G Bassuk; Matthew M Harper; Steven L McKnight; Joseph M Ready; Andrew A Pieper

doi:10.1016/j.celrep.2014.08.030

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P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury

Journal article

Open access

Peer reviewed

P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury

Terry C Yin, Jeremiah K Britt, Héctor De Jesús-Cortés, Yuan Lu, Rachel M Genova, Michael Z Khan, Jaymie R Voorhees, Jianqiang Shao, Aaron C Katzman, Paula J Huntington, …

Cell reports (Cambridge), Vol.8(6), pp.1731-1740

09/25/2014

DOI: 10.1016/j.celrep.2014.08.030

PMCID: PMC4206693

PMID: 25220467

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https://doi.org/10.1016/j.celrep.2014.08.030View

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Abstract

The P7C3 class of neuroprotective aminopropyl carbazoles has been shown to block neuronal cell death in models of neurodegeneration. We now show that P7C3 molecules additionally preserve axonal integrity after injury, before neuronal cell death occurs, in a rodent model of blast-mediated traumatic brain injury (TBI). This protective quality may be linked to the ability of P7C3 molecules to activate nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in nicotinamide adenine dinucleotide salvage. Initiation of daily treatment with our recently reported lead agent, P7C3-S243, 1 day after blast-mediated TBI blocks axonal degeneration and preserves normal synaptic activity, learning and memory, and motor coordination in mice. We additionally report persistent neurologic deficits and acquisition of an anxiety-like phenotype in untreated animals 8 months after blast exposure. Optimized variants of P7C3 thus offer hope for identifying neuroprotective agents for conditions involving axonal damage, neuronal cell death, or both, such as occurs in TBI.

Memory - drug effects

Neuroprotective Agents - therapeutic use

Carbazoles - chemistry

Brain Injuries - drug therapy

Mice, Inbred C57BL

Axons - metabolism

Motor Activity - drug effects

Axonal Transport - drug effects

Blood-Brain Barrier - drug effects

Blood-Brain Barrier - metabolism

Hippocampus - metabolism

Animals

Neuroprotective Agents - pharmacology

Nicotinamide Phosphoribosyltransferase - metabolism

Synaptic Transmission - drug effects

Carbazoles - therapeutic use

Mice

Carbazoles - pharmacology

Disease Models, Animal

Details

Title: Subtitle: P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury
Creators: Terry C Yin - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Jeremiah K Britt - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Héctor De Jesús-Cortés - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA; Graduate Program of Neuroscience, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Yuan Lu - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Rachel M Genova - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Michael Z Khan - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Jaymie R Voorhees - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Human Toxicology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA; Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Jianqiang Shao - Central Microscopy Facility, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Aaron C Katzman - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Paula J Huntington - Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Cassie Wassink - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Latisha McDaniel - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Elizabeth A Newell - Department of Pediatrics, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Laura M Dutca - Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Jacinth Naidoo - Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Huxing Cui - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Alexander G Bassuk - Department of Pediatrics, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA; Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA; Department of Pediatric Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Matthew M Harper - Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA
Steven L McKnight - Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Joseph M Ready - Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Andrew A Pieper - Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA; Department of Neurology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Human Toxicology, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA; Department of Veterans Affairs Center for the Prevention and Treatment of Visual Loss, Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA. Electronic address: andrew-pieper@uiowa.edu
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.8(6), pp.1731-1740
DOI: 10.1016/j.celrep.2014.08.030
PMID: 25220467
PMCID: PMC4206693
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Publisher: United States
Grant note: 5-RO1-MH087986 / NIMH NIH HHS R21 MH100086 / NIMH NIH HHS R01 NS064159 / NINDS NIH HHS 1R21MH100086-01 / NIMH NIH HHS 5R01NS064159-05 / NINDS NIH HHS R01 MH087986 / NIMH NIH HHS I01 RX000427 / RRD VA
Language: English
Date published: 09/25/2014
Academic Unit: Neurology; Molecular Physiology and Biophysics; Psychiatry; Critical Care; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biology; Radiation Oncology; Neuroscience and Pharmacology; Neurology (Pediatrics); Ophthalmology and Visual Sciences
Record Identifier: 9983980059002771

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