Novel Path to Chronic Sensorimotor Dysfunction and Treatment for Chemotherapy

摘要 化疗常伴有神经病理性感觉障碍，可限制或终止治疗和 导致长期残疾。目前的研究支持轴突变性和过度兴奋是潜在的 机械装置。然而，我们最近的研究揭示了一种额外的、绝对新颖的机制，具有 说明化疗相关神经病患者功能丧失的可能性。我们在体内获得了 电生理测量显示来自感觉和神经的神经元信号功能受损 大鼠在接受临床相关的奥沙利铂(OX)方案几周后的运动神经元 化疗。低兴奋性一直表现为明显的失火。 对固定水平的刺激的反应。这一缺陷的特殊性使瞬变激发不受影响， 提示OX治疗可能损害感觉和运动中的钠持续内向电流(NaPIC) 神经元。我们实验室最近发表的发现通过显示药物阻滞剂 NaPIC模拟了OX对持续射击的影响。虽然我们的发现隔离了化疗的慢性影响 在神经兴奋性方面，没有癌症就没有化疗。癌症和牛的疗法可能会起作用 在共同的信号通路(如氧化和炎症)上协同作用，产生神经元低密度脂蛋白 兴奋性。癌症和牛治疗之间相互作用的可能性从我们的 初步报告发现大鼠感觉和运动神经元兴奋性低下显著放大 患有结直肠癌。在这里，我们对我们的工作假设提出了尖锐的测试，即OX治疗是慢性的 通过减少癌症大鼠模型中的NaPIC来损害静态神经元信号。我们将测量火力 OX对肿瘤大鼠感觉和运动神经元行为的在体电生理研究， 为了实现以下四个具体目标：1)测试与癌症相关的相互作用的假设 过程加剧了化疗引起的感觉神经元和运动神经元的低兴奋性；2)测试 假设运动神经元重复放电的慢性缺陷是由于OX诱导的 持续内向电流；3)开发使大鼠感觉神经元和运动神经元放电正常化的疗法 用OX治疗癌症；4)确定与OX诱导的小鼠低兴奋性发展相关的因素 结直肠癌的大鼠模型。这些研究的成功完成将决定：1)第一 在CIPN领域的时间，即OX疗法引起的神经元兴奋性慢性缺陷的程度， 结直肠癌及其组合；2)确定中枢神经系统激发缺陷的生物物理机制 OX治疗后的神经元；3)开发临床前可行的从OX诱导的神经元中拯救神经元的治疗方法 4)在了解OX诱导的低兴奋性的发病机制方面迈出了第一步。 通过将其发展和潜在的生物物理学与感觉和MN基因表达的变化联系起来。

Abstract Chemotherapy is often accompanied by neuropathic sensory disorders that can limit or end treatment and cause long-term disability. Current research supports axon degeneration and hyperexcitability as underlying mechanisms. However, our recent research reveals an additional, absolutely novel mechanism having the potential to account for loss of patient function in chemotherapy-related neuropathy. We obtained in vivo electrophysiological measures which showed functional impairment of neuronal signaling from sensory and motor neurons in rats several weeks after receiving a clinically-relevant regimen of oxaliplatin (OX) chemotherapy. Hypo-excitability was consistently expressed as conspicuous failure to sustain firing in response to fixed levels of stimulation. The specificity of this defect, which leaves transient firing unaffected, suggests that OX treatment may impair sodium persistent inward currents (NaPIC) in sensory and motor neurons. Recent findings published in our lab promote this notion by showing that pharmacological block of NaPIC mimics the effect of OX on sustained firing. While our findings isolate chronic effects of chemotherapy on neuronal excitability, there is no chemotherapy without cancer. Cancer and OX therapy may act synergistically on common signaling pathways (e.g. oxidative and inflammatory) to produce neuronal hypo- excitability. The possibility of an interaction between cancer and OX therapy gains excitement from our preliminary reports that discovered sensory and motor neuron hypo-excitability is significantly amplified in rats with colorectal cancer. Here we propose incisive tests of our working hypothesis that OX treatment chronically impairs static neuronal signaling by reducing NaPIC in a rat model of cancer. We will measure the firing behavior of sensory and motor neurons via in vivo electrophysiological studies of cancer rats treated with OX, in order to achieve the following four specific aims: 1) test the hypothesis that interactions with cancer-related processes exacerbate chemotherapy-induced hypo-excitability in sensory and motor neurons; 2) test the hypothesis that chronic defects in repetitive firing by motor neurons result from an OX-induced decrease in persistent inward current; 3) develop therapy that normalizes firing of sensory and motor neurons in rats treated for cancer with OX; 4) identify factors related to the development of hypo-excitability induced by OX in a rat model of colorectal cancer. Successful accomplishment of these studies will: 1) determine for the first time in the CIPN field, of the extent to which chronic deficits in neuronal excitability arise from OX therapy, colorectal cancer, and their combination; 2) identify biophysical mechanisms underlying firing deficits of a CNS neuron after OX treatment; 3) develop pre-clinically a viable therapy for rescuing neurons from OX-induced firing deficits; 4) take the first step forward in understanding the pathogenesis of OX-induced hypo-excitability by relating its development and underlying biophysics to changes in gene expression of sensory and MNs.