P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage

Cell. 2014 Sep 11;158(6):1324-1334. doi: 10.1016/j.cell.2014.07.040.


The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photocrosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbazoles / pharmacology
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytokines / agonists
  • Cytokines / genetics
  • Cytokines / metabolism
  • Doxorubicin / pharmacology
  • Humans
  • Metabolic Networks and Pathways
  • Mice
  • NAD / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Nicotinamide Phosphoribosyltransferase / genetics
  • Nicotinamide Phosphoribosyltransferase / metabolism


  • Carbazoles
  • Cytokines
  • Neuroprotective Agents
  • P7C3 compound
  • NAD
  • Doxorubicin
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, human