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Cell Rep. 2014 Sep 25;8(6):1731-1740. doi: 10.1016/j.celrep.2014.08.030. Epub 2014 Sep 15.

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

Author information

1
Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
2
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.
3
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.
4
Central Microscopy Facility, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
5
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
6
Department of Pediatrics, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
7
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.
8
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.
9
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.

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.

PMID:
25220467
PMCID:
PMC4206693
DOI:
10.1016/j.celrep.2014.08.030
[Indexed for MEDLINE]
Free PMC Article

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