(PQ9) A novel mechanism of paclitaxel-induced peripheral neuropathy and potential treatment

(PQ9) 紫杉醇诱发周围神经病变的新机制及潜在治疗方法

基本信息

批准号：
9172959
负责人：
Qing Yang
金额：
$ 35.19万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9172959
关键词：
Acute Acute Pain Adult Adverse effects Affect Afferent Neurons Animals Axon Back Behavior Cancer Patient Cancer Survivor Cell Line Chemotherapy-induced peripheral neuropathy Chinese Hamster Ovary Cell Chronic Comorbidity Data Development Electron Microscopy Electrophysiology (science)Epidermis Epilepsy Exposure to FDA approved Fiber Gliosis Goals Histologic Immunohistochemistry In Vitro Inbred BALB C Mice Incidence Infusion procedures Lead Mammary Neoplasms Measures Mechanics Membrane Membrane Potentials Microtubules Mitochondria Modeling Molecular Monitor Morphology Mus Nerve Nerve Degeneration Neurons Nociceptors Oxidative Stress Paclitaxel Pain Pathogenesis Pathologic Processes Pathology Patients Peripheral Peripheral Nervous System Diseases Pharmaceutical Preparations Quality of life Rattus Rodent Role SKBR3 Sensory Skin Source Spinal Cord Survivors Suspension substance Suspensions Symptoms Techniques Testing astrogliosis behavior test channel blockers chemotherapeutic agent chronic pain density effective therapy experience high risk in vivo malignant breast neoplasm member neuron development neuronal excitability neuroprotection neurotoxicity novel overexpression pain behavior painful neuropathy prevent public health relevance sensory neuropathy spontaneous pain taxane therapeutic development therapeutic target tumor

项目摘要

Project summary Paclitaxel-induced peripheral neuropathy (PIPN) and associated neuropathic pain is the most common and serious adverse effect experienced by cancer patients accepted paclitaxel infusion, which adversely affects daily activities and thereby quality of life, and sometimes forces the suspension of treatment, negatively impacting survival. However, mechanisms underlying the pathogenesis of PIPN are uncertain, which hinders the development of effective therapies for this comorbidity. The proposed studies attempt to identify molecular mechanisms underlying PIPN, as well as a potential therapeutic target to prevent the development of PIPN and neuropathic pain. Excessive neuronal excitation is a primary source of PIPN. Our preliminary data indicate that the hyperexcitability of primary sensory neurons might result from paclitaxel-induced inhibition of KCNQ/Kv7 channels, which are abundant in sensory neurons and axons. Retigabine, an FDA-approved drug that opens KCNQ/Kv7 channels, could be a plausible treatment to reduce paclitaxel-induced pathology and symptoms. We hypothesize that paclitaxel induces peripheral neuropathy and chronic pain by inhibiting KCNQ/Kv7 channels and exciting primary sensory neurons, activating KCNQ/Kv7 channels during chemotherapeutic agent infusion may thus prevent the development of PIPN. In this project, we will produce PIPN in adult, tumor-free rats or mice, and utilize techniques of immunohistochemistry, electrophysiology, electron microscopy, and behavioral testing to test three important predictions: 1) Paclitaxel excites primary sensory neurons by inhibiting KCNQ/Kv7 channels. Paclitaxel-induced effects on KCNQ currents in CHO cell lines in which KCNQ2/3 are overexpressed, as well as its effects (KCNQ currents and membrane potential) on DRG neurons from naïve rats, Kcnq2fl/fl//Pax3-Cre, Kcnq3-/-, and their littermate control mice will be assessed electrophysiologically (in vitro recording); 2) Paclitaxel induces peripheral neuropathy and chronic pain by inhibiting KCNQ/Kv7 channels. XE-991, a selective KCNQ/Kv7 channel blocker, will be delivered to naïve rats to see whether XE-991 can simulate PIPN and chronic pain. The role of KCNQ/Kv7 channels in PIPN will then be evaluated by exposing of Kcnq2fl/fl//Pax3-Cre, Kcnq3-/-, and their littermate control mice to paclitaxel. Pain-related behavior, morphological alterations (gliosis in the spinal cord, IENF in the skin, ROS in DRG neurons, mitochondria and microtubules in nerve sections), and neuronal excitability will be assessed; 3) Combining retigabine with paclitaxel can prevent the development of peripheral neuropathy and neuropathic pain. Retigabine will be given to rats during the exposure to paclitaxel. The excitability of DRG neurons, gliosis in spinal cord, IENF in the epidermis, and pain-related behaviors will be measured. Finally, the chemosensitivity of a breast cancer tumor to paclitaxel will be assessed in the presence of retigabine. These studies may lead both to a better understanding of the causes of PIPN as well as delineate novel targets for therapeutic development.

项目摘要紫杉醇引起的周围神经病（PIPN）和相关的神经性疼痛是最常见的，并且癌症患者经历的严重不良反应接受了紫杉醇输注，这每天都会不利影响活动及其生活质量，有时甚至迫使暂停治疗，对生存。但是，PIPN发病机理的基础机制尚不确定，这阻碍了开发这种合并症的有效疗法。拟议的研究试图鉴定分子 PIPN的机制以及防止PIPN和PIPN发展的潜在治疗靶标神经性疼痛。过度的神经元兴奋是PIPN的主要来源。我们指示的初步数据紫杉醇引起的抑制作用可能导致原发性感觉神经元的过度刺激性 KCNQ/KV7通道，有感觉神经元和轴突丰富。 Retigabine，FDA批准打开KCNQ/KV7通道的药物可能是一种合理的治疗方法，可减少紫杉醇诱导的病理和符号。我们假设紫杉醇会诱导周围神经病和通过抑制KCNQ/KV7通道和令人兴奋的主感觉神经元，慢性疼痛，因此，在化学治疗剂输注过程中激活KCNQ/KV7通道可能会预防 PIPN的开发。在这个项目中，我们将在成人，无肿瘤的大鼠或小鼠中生产PIPN，并利用免疫组织化学，电生理学，电子显微镜和行为测试的技术三个重要的预测：1）通过抑制KCNQ/KV7通道，紫杉醇激发原发性神经元。紫杉醇诱导的对KCNQ2/3过表达的CHO细胞系中KCNQ电流的影响，以及它的作用（KCNQ电流和膜电位）对幼稚大鼠的DRG神经元，KCNQ2FL/fl // PAX3-CRE， KCNQ3 - / - 及其同窝控制小鼠将通过电生理评估（体外记录）； 2）紫杉醇通过抑制KCNQ/KV7通道诱导周围神经病和慢性疼痛。 XE-991，a 选择性KCNQ/KV7通道阻滞剂将被输送到幼稚的大鼠，以查看XE-991是否可以模拟PIPN 和慢性疼痛。然后，将通过暴露来评估KCNQ/KV7通道在PIPN中的作用 KCNQ2FL/fl // PAX3-CRE，KCNQ3 - / - 及其同窝控制小鼠到紫杉醇。与疼痛有关的行为，形态学改变（脊髓中的神经病，皮肤中的IENF，DRG神经元中的ROS，线粒体和线粒体中的ROS 神经切片中的微管），将评估神经元兴奋性； 3）将视叶滨与紫杉醇可以防止周围神经病和神经性疼痛的发展。 Retigabine将是在暴露于紫杉醇的过程中给予大鼠。 DRG神经元的兴奋，脊髓的神经胶质病，IENF 将测量表皮和与疼痛相关的行为。最后，乳腺癌的化学敏感性在果酱的存在下，将评估到紫杉醇到紫杉醇的肿瘤。这些研究可能会导致更好了解PIPN的原因以及描绘热发育的新颖目标。