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. ReadyAndrew A. Pieper

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1731-1740
Number of pages10
JournalCell Reports
Volume8
Issue number6
DOIs
StatePublished - Sep 25 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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