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Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):10654-10659. doi: 10.1073/pnas.1809392115. Epub 2018 Sep 26.

Pharmacological bypass of NAD+ salvage pathway protects neurons from chemotherapy-induced degeneration.

Author information

1
Vollum Institute, Oregon Health & Science University, Portland, OR 97239.
2
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 55242.
3
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239.
4
Mitchell Cancer Institute, University of South Alabama, Mobile, AL 33604.
5
Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA 55242; charles-brenner@uiowa.edu goodmanr@ohsu.edu.
6
Vollum Institute, Oregon Health & Science University, Portland, OR 97239; charles-brenner@uiowa.edu goodmanr@ohsu.edu.

Abstract

Axon degeneration, a hallmark of chemotherapy-induced peripheral neuropathy (CIPN), is thought to be caused by a loss of the essential metabolite nicotinamide adenine dinucleotide (NAD+) via the prodegenerative protein SARM1. Some studies challenge this notion, however, and suggest that an aberrant increase in a direct precursor of NAD+, nicotinamide mononucleotide (NMN), rather than loss of NAD+, is responsible. In support of this idea, blocking NMN accumulation in neurons by expressing a bacterial NMN deamidase protected axons from degeneration. We hypothesized that protection could similarly be achieved by reducing NMN production pharmacologically. To achieve this, we took advantage of an alternative pathway for NAD+ generation that goes through the intermediate nicotinic acid mononucleotide (NAMN), rather than NMN. We discovered that nicotinic acid riboside (NAR), a precursor of NAMN, administered in combination with FK866, an inhibitor of the enzyme nicotinamide phosphoribosyltransferase that produces NMN, protected dorsal root ganglion (DRG) axons against vincristine-induced degeneration as well as NMN deamidase. Introducing a different bacterial enzyme that converts NAMN to NMN reversed this protection. Collectively, our data indicate that maintaining NAD+ is not sufficient to protect DRG neurons from vincristine-induced axon degeneration, and elevating NMN, by itself, is not sufficient to cause degeneration. Nonetheless, the combination of FK866 and NAR, which bypasses NMN formation, may provide a therapeutic strategy for neuroprotection.

KEYWORDS:

NAD+; axon degeneration; chemotherapy-induced peripheral neuropathy; nicotinamide mononucleotide; nicotinic acid riboside

PMID:
30257945
PMCID:
PMC6196523
DOI:
10.1073/pnas.1809392115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: C.B. owns stock in and consults for ChromaDex, Inc., and consults for Cytokinetics, Inc. M.E.M. has consulted for ChromaDex, Inc.

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