Direct assessment of distal small fiber neuropathy in models of neurotoxicity

描述（由申请人提供）：本提案旨在通过开发一种新的电生理方法来直接，无创地评估小直径轴突（A4和C纤维）的传导，从而提高小纤维毒性神经病（SFTN）动物模型的敏感性，特异性和有效性。这些纤维的损伤是神经毒性暴露（如化疗、工业或环境毒性）引起的疼痛、热敏性丧失和自主神经缺陷的关键组成部分。可用于SFTN的模型有限，并且对这些异常的病理生理知之甚少。概述的研究将应用多单元记录技术，最初用于测量中枢神经系统的皮质内传导，以评估周围神经系统的缓慢（小于2.5米/秒）和异步活动。他们还采用高频刺激技术来评估小直径轴突特别容易受到局部能量利用和储备不足的影响。概述的方法将用于探讨SFTN在两种不同的中毒性神经病动物模型中的作用：伊沙比酮（IXA），一种新的微管稳定剂，和辣椒素（CAP），一种局部止痛药。IXA损害大直径和小直径轴突和神经病变是这种新的抗癌治疗的严重剂量限制因素。概述的研究将侧重于不同纤维类型的缺陷的开始、模式、大小和恢复程度的差异，重点是以前未记载的SFTN变化。据我们所知，这将是首次对ixa诱导的神经病变动物模型进行全面研究。CAP以含p物质的轴突为靶点，引起排他的SFTN。这些研究将集中于表皮内感觉轴突极端末端区域活性的非侵入性功能生物标志物的开发。无创测量小直径有髓和无髓轴突的传导将为评估表皮内神经纤维密度（IENFD）提供一种替代和/或补充的测量方法。在每个模型中，SFTN将在尾神经和指神经的最远端段使用表面非侵入性手术进行评估。电生理数据将与神经纤维（A12、A4和C纤维）沿远端到近端梯度的全光谱的组织病理学变化进行比较。如果成功，概述的研究将扩大神经传导测量的效用，并将为SFTN提供新的客观和敏感的生物标志物。因此，概述的研究将大大提高现有的各种毒性神经病动物模型的效用，包括与化疗相关的动物模型，并将为许多人类疾病（包括糖尿病、艾滋病和遗传性神经病）相关的神经损伤的临床和临床前评估提供新的工具。这些研究将为毒素诱导或疾病相关的小直径有髓鞘和无髓鞘轴突（A4和C纤维）功能缺陷提供一种新的生物标志物。尽管这些轴突在处理疼痛、热敏性和自主神经功能中起着关键作用，并且是大多数神经中主要的纤维类型，但现有技术对它们的测量很差，因此研究不足。如果成功，这些研究将大大提高现有各种毒性神经病（包括与化疗相关的神经病）动物模型的实用性，并将为许多人类疾病（包括糖尿病、艾滋病和遗传性神经病）相关神经损伤的临床和临床前评估提供新的工具。

DESCRIPTION (provided by applicant): This proposal is designed to improve the sensitivity, specificity and validity of animal models of small fiber toxic neuropathy (SFTN) by developing a novel electrophysiological method for the direct, non-invasive assessment of conduction in small diameter axons (A4 and C fibers). Damage to these fibers is a key component of pain, the loss of thermal sensitivity and autonomic deficits induced by neurotoxic exposures (e.g., chemotherapy, industrial or environmental toxicity). Available models for SFTN are limited and the pathophysiology of these abnormalities is poorly understood. The outlined studies will apply a technique of multiple unit recordings, originally developed to measure intracortical conduction in the central nervous system, to the assessment of slow (less than 2.5 m/sec) and asynchronous activity in peripheral nervous system. They also employ techniques of high frequency stimulation to evaluate the hypothesis that small diameter axons are especially vulnerable to deficits in local energy utilization and reserves. The outlined methods will be used to explore SFTN in two distinct animal models of toxic neuropathy: ixabepilone (IXA), a new microtubule-stabilizing agent, and capsaicin (CAP), a local analgesic. IXA impairs both large and small diameter axons and neuropathy is a serious dose-limiting factor of this new anti-cancer treatment. The outlined studies will focus on differences in the onset, pattern, magnitude and degree of recovery of deficits across fiber types, with an emphasis on previously undocumented changes in SFTN. To our knowledge these will be the first comprehensive investigations of animal models of IXA-induced neuropathy. CAP targets substance P-containing axons and evokes an exclusive SFTN. These studies will focus on the development of a non-invasive functional biomarker of activity in the extreme terminal regions on intraepidermal sensory axons. The non-invasive measurement of conduction in small diameter myelinated and unmyelinated axons would provide an alternative and/or complementary measure to the assessment of intraepidermal nerve fiber density (IENFD). In each model, SFTN will be evaluated using surface non-invasive procedures in the most distal segments of both the caudal and digital nerves. Electrophysiological data will be compared to the histopathological changes in a full spectra of nerve fibers (A12, A4 and C fibers) along a distal-to- proximal gradient. If successful, the outlined studies will expand the utility of nerve conduction measures and will provide a new objective and sensitive biomarker for SFTN. The outlined studies will thus greatly improve the utility of existing animal models of a variety of toxic neuropathies, including those associated with chemotherapy, and will provide a new tool for the clinical and preclinical assessment of nerve damage associated with many human diseases including diabetes, AIDS, and genetic neuropathies. PUBLIC HEALTH RELEVANCE: Project Narrative These studies will provide a novel biomarker for toxin-induced or disease-related deficits in the function of small diameter myelinated and unmyelinated axons (A4 and C fibers). Although these axons play a key role in processing pain, thermal sensitivity and autonomic function and are the predominant fiber type in most nerves, they are poorly measured by existing techniques and are therefore understudied. If successful, the outlined studies will greatly improve the utility of existing animal models of a variety of toxic neuropathies, including those associated with chemotherapy, and will provide a new tool for the clinical and preclinical assessment of nerve damage associated with many human diseases including diabetes, AIDS, and genetic neuropathies.