# Mechanistic Studies of the Natural Product Nicotinamide Riboside for Relief of Painful Sensory Neuropathy

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $428,905

## Abstract

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-naïve 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 naïve 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...

## Key facts

- **NIH application ID:** 9852424
- **Project number:** 5R01AT009705-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** DONNA L HAMMOND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $428,905
- **Award type:** 5
- **Project period:** 2018-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852424

## Citation

> US National Institutes of Health, RePORTER application 9852424, Mechanistic Studies of the Natural Product Nicotinamide Riboside for Relief of Painful Sensory Neuropathy (5R01AT009705-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9852424. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*