Cell Reports
Volume 8, Issue 6, 25 September 2014, Pages 1731-1740
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Report
P7C3 Neuroprotective Chemicals Block Axonal Degeneration and Preserve Function after Traumatic Brain Injury

https://doi.org/10.1016/j.celrep.2014.08.030Get rights and content
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open access

Highlights

  • Treatment with (−)-P7C3-S243 after blast injury blocks widespread axonal degeneration

  • Treatment with (−)-P7C3-S243 after blast injury preserves learning and memory

  • Treatment with (−)-P7C3-S243 after blast injury preserves motor coordination

  • Without treatment, neuropsychiatric deficits persist chronically after blast injury

Summary

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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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Co-first author