Continuing advances in detection and treatment have greatly increased the number of cancer survivors, as well as more Veterans living with cancer because of continued therapy. However, while these therapies prolong life, they are accompanied by adverse effects that introduce functional limitations and significantly reduce quality of life of Veterans. For example, taxane and platinum-based chemotherapies produce very painful and debilitating peripheral neuropathies that greatly diminish patients? quality of life. These agents can also cause dry eye syndrome (DES), and in the case of platinum-based therapies, hearing loss and tinnitus due to ototoxicity in 40-80% of adults. Currently, no effective treatment exists to reduce the incidence of these debilitating side effects of therapy and they remain a significant unmet need in healthcare. In recent years, evidence has accrued that nicotinamide adenine dinucleotide (NAD+), an essential redox coenzyme, plays an important role in protection against axonal injury. This laboratory recently demonstrated that a naturally occurring vitamin B3 precursor of NAD+, nicotinamide riboside (NR; NIAGEN) can both prevent and reverse paclitaxel-induced peripheral neuropathy in rodents. The main goal of this application is to obtain preclinical data to evaluate the ability NR to improve the quality of life and function of Veterans with cancer as well as cancer survivors who suffer the sequelae of chemotherapy. The proposed studies will focus on a platinum compound, cisplatin, that is associated with a high incidence of painful peripheral neuropathy, as well as ocular toxicity, and ototoxicity.
The first aim of this proposal will determine whether prophylactic treatment with NR prevents cisplatin-induced allodynia (hypersensitivity) to tactile and cool stimuli, as well as blunts the aversive/affective dimension of the neuropathy. Hypersensitivity to tactile and cool stimuli will be assessed in vehicle- and NR-treated rats by determining threshold to withdrawal from application of calibrated von Frey filaments or a cool stimulus to the hind paw. The place escape avoidance paradigm will be used to assess changes in the aversive/affective components of nociception.
The second aim of the proposal will determine whether prophylactic treatment with NR can prevent photophobia (light aversion), as well as corneal hypersensitivity and deficits in tear production induced by cisplatin. Photophobia will be assessed in vehicle- and NR-treated rats by measuring time spent in a brightly-lit chamber, while corneal hypersensitivity will be assessed by changes in withdrawal responses to tactile stimulation of the cornea or degree of squinting induced by application of hyperosmolar saline drops. Reflex and basal tear production will be assessed by Schirmer's test.
The final aim of this proposal will determine whether prophylactic treatment with NR can prevent cisplatin-induced loss of hearing. Cochlear function will be assessed in vehicle- and NR-treated rats by distortion product otoacoustic emissions, and functionality of central nervous system auditory pathways will be assessed by auditory brainstem responses. These experiments will be conducted in both male and female rats to assess possible sex-dependent differences. The three aims will be conducted in parallel because they are not dependent on one another. Moreover, a positive outcome in any one would support a clinical trial of a treatment that could be prevent chemotherapy-induced disabilities in Veterans and substantially improve their quality of life. This work addresses an unmet need in healthcare and has the potential to be transformative for the patient and clinician alike.
Over 45,000 Veterans are newly diagnosed with cancer each year. Many will be administered platinum-based chemotherapy as first-line treatment. However, these compounds are particularly toxic and Veterans receiving treatment will suffer disabling side-effects that include neuropathies characterized by numbness, dysesthesia, pain, and loss of proprioception, as well as dry-eye syndrome. The majority will also experience irreversible hearing loss, a life-altering disability. This study will use a rodent model of cisplatin-induced chemotherapy to evaluate the ability of a vitamin B3 precursor of NAD+, nicotinamide riboside, to prevent the occurrence of peripheral neuropathy, dry-eye syndrome, and loss of hearing. No evidence-based treatments for these ad- verse effects of cisplatin chemotherapy are available. A finding that nicotinamide riboside prevents any one or all of these adverse effects strongly support clinical trials, the results of which could be transformative for Vet- erans undergoing chemotherapy leading to an improved quality of life and preventing a life-altering disability.
