nicotinamide-beta-riboside and Peripheral-Nervous-System-Diseases

Nicotinamide riboside (NR) is a vitamin B3 precursor of NAD that blunts diabetic and chemotherapy-induced peripheral neuropathy in preclinical models. This study examined whether NR also blunts the loss of intraepidermal nerve fibers induced by paclitaxel, which is associated with peripheral neuropathy. The work was conducted in female rats with N-methyl-nitrosourea (MNU)-induced tumors of the mammary gland to increase its translational relevance, and to assess the interaction of NR with paclitaxel and NR's effect on tumor growth. Once daily oral administration of 200 mg/kg NR p.o. beginning with the first of 3 i.v. injections of 6.6 mg/kg paclitaxel to tumor-bearing rats significantly decreased paclitaxel-induced hypersensitivity to tactile and cool stimuli, as well as place-escape avoidance behaviors. It also blunted the loss of intraepidermal nerve fibers in tumor-bearing rats, as well as a separate cohort of tumor-naive rats. Unexpectedly, concomitant administration of NR during paclitaxel treatment further decreased tumor growth; thereafter, tumor growth resumed at the same rate as vehicle-treated controls. Administration of NR also decreased the percentage of Ki67-positive tumor cells in these rats. Once daily administration of NR did not seem to alter tumor growth or the percentage of Ki67-positive tumor cells in rats that were not treated with paclitaxel and followed for 3 months. These results further support the ability of NR to play a protective role after nerve injury. They also suggest that NR may not only alleviate peripheral neuropathy in patients receiving taxane chemotherapy, but also offer an added benefit by possibly enhancing its tumor-suppressing effects.

Topics: Animals; Female; Neoplasms; Niacinamide; Paclitaxel; Peripheral Nervous System Diseases; Pyridinium Compounds; Rats

Injury to sensory afferents may contribute to the peripheral neuropathies that develop after administration of chemotherapeutic agents. Manipulations that increase levels of nicotinamide adenine dinucleotide (NAD) can protect against neuronal injury. This study examined whether nicotinamide riboside (NR), a third form of vitamin B3 and precursor of NAD, diminishes tactile hypersensitivity and place escape-avoidance behaviors in a rodent model of paclitaxel-induced peripheral neuropathy. Female Sprague-Dawley rats received 3 intravenous injections of 6.6 mg/kg paclitaxel over 5 days. Daily oral administration of 200 mg/kg NR beginning 7 days before paclitaxel treatment and continuing for another 24 days prevented the development of tactile hypersensitivity and blunted place escape-avoidance behaviors. These effects were sustained after a 2-week washout period. This dose of NR increased blood levels of NAD by 50%, did not interfere with the myelosuppressive effects of paclitaxel, and did not produce adverse locomotor effects. Treatment with 200 mg/kg NR for 3 weeks after paclitaxel reversed the well-established tactile hypersensitivity in a subset of rats and blunted escape-avoidance behaviors. Pretreatment with 100 mg/kg oral acetyl-L-carnitine (ALCAR) did not prevent paclitaxel-induced tactile hypersensitivity or blunt escape-avoidance behaviors. ALCAR by itself produced tactile hypersensitivity. These findings suggest that agents that increase NAD, a critical cofactor for mitochondrial oxidative phosphorylation systems and cellular redox systems involved with fuel utilization and energy metabolism, represent a novel therapeutic approach for relief of chemotherapy-induced peripheral neuropathies. Because NR is a vitamin B3 precursor of NAD and a nutritional supplement, clinical tests of this hypothesis may be accelerated.

Topics: Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Eosinophils; Escape Reaction; Female; Hyperalgesia; Leukocyte Count; Locomotion; NAD; Neutrophils; Niacinamide; Nociception; Paclitaxel; Pain Measurement; Peripheral Nervous System Diseases; Pyridinium Compounds; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Time Factors