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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 42; pp. 10654 - 10659
• Main Authors: Liu, Hui-wen, Smith, Chadwick B., Schmidt, Mark S., Cambronne, Xiaolu A., Cohen, Michael S., Migaud, Marie E., Brenner, Charles, Goodman, Richard H.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.10.2018
• Subjects: Acrylamides - pharmacology; Animals; Antineoplastic Agents, Phytogenic - toxicity; Biological Sciences; Drug Combinations; Francisella tularensis - enzymology; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Ganglia, Spinal - pathology; NAD - metabolism; Nerve Degeneration - chemically induced; Nerve Degeneration - metabolism; Nerve Degeneration - prevention & control; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Nicotinamide Mononucleotide - analogs & derivatives; Nicotinamide Mononucleotide - metabolism; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors; Nicotinamide Phosphoribosyltransferase - metabolism; Piperidines - pharmacology; Vincristine - toxicity; NAD; nicotinic acid riboside; nicotinamide mononucleotide; axon degeneration; chemotherapy-induced peripheral neuropathy
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1809392115

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.