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

Héctor J De Jesús-Cortés's picture
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TitleP7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury.
Publication TypeJournal Article
Year of Publication2014
AuthorsYin, TC, Britt, JK, De Jesús-Cortés, H, Lu, Y, Genova, RM, Khan, MZ, Voorhees, JR, Shao, J, Katzman, AC, Huntington, PJ, Wassink, C, McDaniel, L, Newell, EA, Dutca, LM, Naidoo, J, Cui, H, Bassuk, AG, Harper, MM, McKnight, SL, Ready, JM, Pieper, AA
JournalCell Rep
Volume8
Issue6
Pagination1731-40
Date Published2014 Sep 25
ISSN2211-1247
KeywordsAnimals, Axonal Transport, Axons, Blood-Brain Barrier, Brain Injuries, Carbazoles, Disease Models, Animal, Hippocampus, Memory, Mice, Mice, Inbred C57BL, Motor Activity, Neuroprotective Agents, Nicotinamide Phosphoribosyltransferase, Synaptic Transmission
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.

DOI10.1016/j.celrep.2014.08.030
Alternate JournalCell Rep
PubMed ID25220467
PubMed Central IDPMC4206693
Grant List1R21MH100086-01 / MH / NIMH NIH HHS / United States
5-RO1-MH087986 / MH / NIMH NIH HHS / United States
5R01NS064159-05 / NS / NINDS NIH HHS / United States
R01 MH087986 / MH / NIMH NIH HHS / United States