Certain chemotherapy drugs cause peripheral neuropathy, a condition marked by nerve damage that causes pain, numbness, tingling, swelling, or muscle weakness. An early feature of chemotherapy-induced peripheral neuropathy is axon degeneration, thought to be caused by the loss of the essential metabolite nicotinamide adenine dinucleotide (NAD+).
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.
Authors hypothesized that protection could similarly be achieved by reducing NMN production pharmacologically. To achieve this, they took advantage of an alternative pathway for NAD+ generation that goes through the intermediate nicotinic acid mononucleotide (NAMN), rather than NMN.
The authors treated rat dorsal root ganglion neurons with the chemotherapy drug vincristine and a combination of compounds, namely FK866 (an inhibitor of the enzyme nicotinamide phosphoribosyltransferase that produces NMN) and nicotinic acid riboside (NAR), a precursor of NAMN. Compared with vincristine alone, the combination treatment reduced NMN levels without significantly altering NAD+ levels, which were substantially lower than in untreated neurons.
Moreover, combined treatment with FK866 and NAR protected neurons against vincristine-induced axon degeneration as effectively as the bacterial enzyme NMN deamidase. According to the authors, the combination of FK866 and NAR may provide an effective strategy for preventing chemotherapy-induced peripheral neuropathy.
http://www.pnas.org/content/early/2018/09/25/1809392115
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