NICOTINAMIDE RIBOSIDE FOR THE TREATMENT OF CHEMOTHERAPY-INDUCED NEUROPATHY, DRY EYE SYNDROME, AND HEARING LOSS

在检测和治疗方面的不断进步大大增加了癌症幸存者的数量，因为 以及更多因持续治疗而患癌症的退伍军人。然而，虽然这些疗法 延长生命，它们伴随着不良反应，导致功能限制和显著 降低退伍军人的生活质量。例如，紫杉烷和以铂为基础的化疗产生非常多的 疼痛和虚弱的周围神经病变，极大地降低了患者的生活质量。这些代理可以 也会导致干眼综合症(DES)，在以铂为基础的治疗中，会导致听力损失和耳鸣 由于40%-80%的成年人耳毒性。目前，还没有有效的治疗方法来减少这些疾病的发生率。 治疗的副作用使人衰弱，它们仍然是医疗保健中一个重要的未得到满足的需求。近年来， 已有证据表明，烟酰胺腺嘌呤二核苷酸(NAD+)是一种重要的氧化还原辅酶，在 在保护轴突损伤中发挥重要作用。这个实验室最近证明了一种自然的 NAD+的维生素B3前体烟酰胺核苷(NIAGEN®)既可以预防也可以逆转 紫杉醇诱导的啮齿动物周围神经病变。此应用程序的主要目标是获得临床前 评价退伍军人癌症患者生活质量和功能的能力 遭受化疗后遗症的癌症幸存者。拟议的研究将集中在铂金上。 顺铂，它与痛性周围神经病变和眼部疼痛的高发病率有关 毒性和耳毒性。这项提案的第一个目标将决定是否使用NR进行预防性治疗 防止顺铂引起的触觉和冷刺激超敏(超敏)，以及钝化 神经病的厌恶/情感维度。对触觉和冷刺激的过敏性将在 用校正的von Frey确定停用Von Frey的阈值 花丝或对后爪的凉爽刺激。将使用地点逃生避免范例来评估 痛觉的厌恶/情感成分的变化。提案的第二个目标将决定 使用NR预防性治疗是否可以预防畏光(避光)以及角膜 顺铂引起的泪液分泌过敏和泪液分泌缺陷。恐光症将在车辆中进行评估- 和NR治疗的大鼠，通过测量在明亮的室内度过的时间，同时角膜过敏将 根据对角膜触觉刺激或斜视程度的退缩反应的变化进行评估 应用高渗盐水滴入所致。反射和基础泪液产生将通过以下方法进行评估 席尔默试验。这项提案的最终目标将决定使用NR进行预防性治疗是否可以 预防顺铂引起的听力损失。将通过以下方法评估赋形剂和天然药物处理的大鼠的耳蜗功能 失真产物耳声发射和中枢神经系统听觉通路的功能 通过听觉脑干反应进行评估。这些实验将在雄性和雌性大鼠身上进行。 以评估可能的性别依赖差异。这三个目标将并行进行，因为它们是 互不依赖的。此外，任何一项的阳性结果都将支持一项临床试验 可以预防退伍军人化疗所致残疾并显著改善他们的 生活质量。这项工作解决了医疗保健领域未得到满足的需求，并有可能对 病人和临床医生一样。

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.