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

这个项目试图更好地了解痛性周围神经病的潜在机制，以及 特别是寻找一种新的策略来缓解化疗引起的周围神经病(CIPN) 目前还没有有效的治疗方法。事实上，CIPN可能是如此痛苦，以至于有必要减少 药物剂量，推迟化疗，甚至停止治疗。此外，周围神经病变可能 而不是随着时间的推移而解决。CIPN的剂量限制性和持久性是一个重要的保健问题。 柠檬。该领域的许多研究都是由以下假设推动的：表皮内神经纤维(IENF)的丢失、损伤 背根神经节初级传入神经元与神经胶质细胞和巨噬细胞的激活 紫杉烷诱导的CIPN，包括对线粒体功能障碍的关注。如果没有一个经纪人可以 预防机械过敏和疼痛的厌恶维度，不可能确定 这些机制是CIPN的原因，或者是为了检验线粒体功能障碍是一种不充分- ING机制。我们建议使用烟酰胺核苷(NR)，这是一种天然的维生素B3前体 NAD+可以纠正线粒体功能障碍，作为一种研究工具。我们证明了一剂NR 提高NAD+水平可以改善机械过敏和疼痛的厌恶维度 紫杉醇对肿瘤幼稚雌性大鼠的影响。相比之下，NR并不能减轻感觉神经病的结果- 死于弗兰克神经损伤。这种差异效应为严格的比较分析打开了大门 NR减轻感觉神经病的作用机制。这项提案将首先将调查结果扩展到 对紫杉醇诱导的CIPN荷瘤雌性大鼠的保护作用。其次，它将确认NR不会抑制 SNI大鼠的神经病变。第三，它将把NR的不同作用与NAD+的损伤特异性变化联系起来 定位紫杉醇处理大鼠背根神经节神经元的生物合成酶利用NR纠正缺血-再灌注损伤 CTS，而这一途径在SNI后不可用，并通过测量NAD+来支持这些研究 背根神经节和远端神经。第四，它将表征Biosyn.的转录本和蛋白质的分布 不同类型背根节神经元之间的合成酶并确定紫杉醇如何改变它们 在肿瘤幼稚和荷瘤大鼠中，以及在SNI大鼠中。第五，它将确定NR是否可以防止损失 IENF的改变，特定神经元群体的丧失，以及DRG中神经胶质细胞和巨噬细胞的激活。 拟议的研究将检验NR的保护作用是由NAD+和LINK介导的假设 这与其对初级感觉神经元特定亚群的保护作用，防止IEFN的丢失， DRG内巨噬细胞和卫星细胞的激活。这项工作将增加我们对 不同类型痛性感觉神经病的基础机制，可能指导 新的治疗方法，以解决肿瘤学中一个重要的未得到满足的需求，并提供了与 为什么这种天然产品可能不是所有类型的感觉神经病的通用治疗方法。

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 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.