This project seeks to better understand the mechanisms that underlie painful peripheral neuropathy, and particularly to identify a new strategy to relieve chemotherapy-induced peripheral neuropathies (CIPN) for which there are no efficacious treatments. Indeed, CIPN may be so painful that it is necessary to reduce the dose of agent, delay chemotherapy, or even cease treatment. Furthermore, the peripheral neuropathies may not resolve with time. The dose-limiting nature and the persistence of CIPN are significant health care prob- lems. Much research in the field is driven by hypotheses that loss of intraepidermal nerve fibers (IENF), injury to primary afferent neurons and activation of glial cells and macrophage in the dorsal root ganglion (DRG) underlie taxane-induced CIPN, including a focus on mitochondrial dysfunction. Without an agent that can prevent mechanical hypersensitivity and the aversive dimension of pain, it is not possible to establish that these mechanisms are causative of CIPN or to test the hypothesis that mitochondrial dysfunction is an underly- ing mechanism. We propose to use nicotinamide riboside (NR), a natural product vitamin B3 precursor of NAD+ that can correct mitochondrial dysfunction, as an investigational tool. We show that a dose of NR that increases NAD+ levels can ameliorate the mechanical hypersensitivity and the aversive dimension of pain caused by paclitaxel in tumor-nave female rats. In contrast, NR does not alleviate sensory neuropathy result- ing from frank nerve injury. This differential effect opens the door to rigorous comparative analyses of the mechanisms by which NR acts to alleviate sensory neuropathy. This proposal will first extend the findings with NR to paclitaxel-induced CIPN in tumor-bearing female rats. Second, it will confirm that NR does not suppress neuropathy in rats with SNI. Third, it will relate the differential actions of NR to injury specific changes in NAD+ biosynthetic enzymes that position DRG neurons in paclitaxel treated rats to make use of NR to correct defi- cits, whereas this pathway is not available after SNI, and support these studies with measurement of NAD+ in the DRG and distal nerve. Fourth, it will characterize the distribution of transcripts and protein for the biosyn- thetic enzymes among the different classes of DRG neurons and determine how they are altered by paclitaxel in tumor nave and tumor-bearing rats, as well in SNI rats. Fifth, it will determine whether NR prevents the loss of IENF, loss of specific neuron populations, as well as activation of glial cells and macrophages in the DRG. The proposed studies will test the hypothesis that the protective effects of NR are mediated by NAD+ and link this to its protective effects on specific subpopulations of primary sensory neurons, the prevention of IEFN loss, and activation of macrophages and satellite cells in DRG. This work will increase our understanding of the mechanisms that underlie different types of painful sensory neuropathy, possibly guide the development of a new treatment to address a significant unmet need in oncology, and just as importantly provide a rationale as to why this natural product may not be a universal treatment for all types of sensory neuropathy.
Painful peripheral neuropathies are difficult to treat and a significant health care problem, particularly in the case of chemotherapy-induced peripheral neuropathies (CIPN) for which there are no evidence-based treatments. The finding that the natural product nicotinamide riboside, a vitamin B3 precursor of NAD+ that can correct mitochondrial dysfunction, ameliorates CIPN but not sensory neuropathy produced by frank nerve injury provides a unique opportunity to rigorously test several hypotheses concerning the mechanism of CIPN and other neuropathies. The results may lead to a better understanding of the mechanisms of CIPN, development of the first effective treatment for CIPN, and insight into why nicotinamide riboside will not be a universal treatment for all types of painful sensory neuropathies.