title: P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury.
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.
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Terry C
authors.initials: TC
authors.lastname: Yin
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Jeremiah K
authors.initials: JK
authors.lastname: Britt
authors.affiliation: 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.
authors.forename: Héctor
authors.initials: H
authors.lastname: De Jesús-Cortés
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Genova
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: Khan
authors.affiliation: 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.
authors.forename: Jaymie R
authors.initials: JR
authors.lastname: Voorhees
authors.affiliation: Central Microscopy Facility, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Katzman
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Huntington
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Cassie
authors.initials: C
authors.lastname: Wassink
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Latisha
authors.initials: L
authors.lastname: McDaniel
authors.affiliation: Department of Pediatrics, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Newell
authors.affiliation: 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.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Dutca
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Jacinth
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Huxing
authors.initials: H
authors.lastname: Cui
authors.affiliation: 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.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
authors.affiliation: 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.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Harper
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: McKnight
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ready
authors.affiliation: 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.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D001369:Axons / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D002227:Carbazoles; D018696:Neuroprotective Agents; C552520:P7C3 compound; D054409:Nicotinamide Phosphoribosyltransferase