Prevention and treatment of paclitaxel-induced peripheral neuropathy

化疗引起的周围神经病变（CIPN）是一种使人衰弱的疾病， 对大量癌症患者的毁灭性影响。根据疾病控制中心和 在美国，每年有65万患者接受化疗， 这些患者中有70%会出现CIPN症状。临床研究表明，CIPN是一种领先的 导致治疗不依从、生活质量降低和癌症存活率降低。的患者 相比之下，出现症状性CIPN的总治疗费用也增加了20，000美元 给那些没有症状的病人，也更容易复发。目前 CIPN尚无既定治疗方法。 4-氨基吡啶（4-aminopyridine，4AP）是一种钾离子通道抑制剂， 预防和/或治疗CIPN。与已知的4AP在轴突中实现脉冲传导的能力不同， 髓磷脂损伤，4AP最近已被用于治疗急性周围神经损伤，具有增强的耐久性， 髓鞘损伤的功能恢复和修复。在最近的研究中， 4AP增强皮肤神经元素的愈合和再生。此外，在其最好的研究应用中， 4AP用于缓解多种神经系统综合征的症状，其中正常神经细胞 功能受损。恢复正常的神经功能也可能与减少神经性疼痛有关， 如先前在患有慢性脊髓损伤的个体中的研究所见。 该建议的过度假设是，4AP可用于预防或减少 紫杉醇（PTX）引起的。我们的实验将测试独立的子假设，（i） 在CIPN建立之前开始4AP治疗可以防止其发展，而不会损害 PTX在治疗小鼠乳腺癌的公认同基因模型中的有效性;和（ii）建立 CIPN对4AP有反应，作为CIPN建立后减少神经性疼痛的手段。 PTX诱导的CIPN的已建立小鼠模型将用于这些实验中。4AP将是 研究了作为与PTX同时治疗以预防CIPN发展，以及作为提供 在已建立的CIPN中症状缓解。结局将评价压力敏感性（异常性疼痛）、热敏感性 敏感性，步态协调，电生理学，肌肉生理学和组织学，重点是超微结构 变化

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition with potentially devastating effects on large numbers of cancer patients. According to the Centers for Disease Control and Prevention, 650,000 patients are treated with chemotherapy every year in the United States, and between 30- 70% of these patients will develop symptoms of CIPN. Clinical research has demonstrated CIPN is a leading cause of therapeutic non-compliance, reduced quality of life and poorer cancer survival rates. Patients who develop symptomatic CIPN also have an associated $20,000 increase in overall treatment cost in comparison to patients that do not develop symptoms and are also more like to suffer relapse of their cancer. Currently, there are no established treatments for CIPN. We propose that 4-aminopyridine (4AP), principally a K+ channel inhibitor, is a promising candidate to prevent and/or treat CIPN. Separate from the known abilities of 4AP to enable impulse conduction in axons with myelin damage, 4AP has recently been used to treat acute peripheral nerve injuries with enhanced durable functional recovery and repair of myelin damage. In more recent studies, treatment of acute skin wounds with 4AP enhances healing and regeneration of neural elements of skin. In addition, in its best studied applications, 4AP is used to provide symptomatic relief in a variety of neurological syndromes in which normal nerve cell function is compromised. Restoring normal nerve function may also be relevant to decreasing neuropathic pain, as seen in previous studies in individuals with chronic spinal cord injury. The over-arching hypothesis of this proposal is that 4AP can be used to prevent or decrease caused by exposure to paclitaxel (PTX). Our experiments will test the independent sub-hypotheses that (i) initiation of 4AP treatment prior to establishment of CIPN prevents its development without compromising the effectiveness of PTX in treating a well-accepted syngeneic model of breast cancer in mice; and (ii) established CIPN is responsive to 4AP as a means of decreasing neuropathic pain after CIPN is established. An established mouse model for PTX-induced CIPN will be used in these experiments. 4AP will be studied both as a concurrent treatment with PTX to prevent CIPN development, and as a means of providing symptomatic relief in established CIPN. Outcomes will evaluate the pressure sensitivity (allodynia), thermal sensitivity, gait coordination, electrophysiology, muscle physiology, and histology focusing on the ultrastructural changes.