Editors' ChoiceNeurodegeneration

Neuroprotective Drug Gives a Nod to NAD

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Science Translational Medicine  01 Oct 2014:
Vol. 6, Issue 256, pp. 256ec169
DOI: 10.1126/scitranslmed.3010418

Abnormal function and death of neurons lie at the heart of many neurodegenerative diseases, as well as conditions such as stroke, traumatic brain injury, and neonatal hypoxia-ischemia. No available therapeutics have been proven to prevent or even slow neuronal death in many of these diseases. In 2010, researchers used in vivo screening to identify a new class of molecules, termed aminopropyl carbazoles, which enhanced growth of new nerve cells in the hippocampus of mouse brain. A particular compound from this group, P7C3, was found to be orally bioavailable, and readily crossed the blood-brain barrier and strongly enhanced neurogenesis by preventing death of newborn neurons. Subsequently, it was shown that P7C3 could prevent neuronal death in models of Parkinson’s disease, amyotrophic lateral sclerosis, and traumatic brain injury. However, the mechanism of P7C3’s efficacy remained a mystery, hampering further development.

To address this mechanistic question, the same group of researchers recently synthesized a derivative of P7C3, which was amenable to photocrosslinking as well as CLICK chemistry. This allowed them to crosslink P7C3 to its protein targets, isolate these covalently-modified proteins, and then identify them using 2D gel electrophoresis and mass spectrometry. Using this method, Wang et al. identified nicotinamide phosphoribosyltransferase (NAMPT) as a key target of P7C3 action. NAMPT is the rate-limiting enzyme in the production of the metabolite NAD+, which is critical for neuronal survival and the function of many enzymes, including the neuroprotective sirtuin proteins. A decline in NAMPT function has been implicated in the pathogenesis of aging, and can hasten neuronal death. Wang et al. demonstrated that P7C3 enhanced NAMPT activity and prevented NAD+ depletion and death of cells treated with doxorubicin. This discovery supports the existing data suggesting that bolstering NAD+ production can be neuroprotective, and provides a critical reagent for future research, as well as a drug candidate for human studies. Whereas P7C3 has not yet been tested in humans and may not survive the drug development process, this discovery firmly establishes the NAMPT-NAD+ pathway as a viable and potentially tractable therapeutic target for developing drugs to treat neurodegenerative diseases.

G. Wang et al., P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. Cell 158, 1324–34 (2014). [Abstract]

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