Mechanisms underlying spontaneous firing by motoneurons with acute neurotoxicity

摘要 化疗中常用的铂基化合物(PBCs)的毒性作用与其 有用性是成功抗击致命癌症的主要选择。选择生存的决定 使世界各地的人们遭受PBC神经毒性的折磨，这种毒性通过引起神经功能障碍而降低生活质量 在治疗期间和治疗后很长一段时间内都会出现障碍。疼痛、奇怪的感觉、疲劳和平衡困难 和行走是常见的症状，统称为化疗引起的神经病(CIN)。在.期间 在治疗过程中，观察到感觉神经元和运动神经元都被无意地放电，即它们表现出自发的 解雇(SA)，有证据表明SA对最早的痛苦迹象负有责任，包括 肌肉不受控制的收缩、抽筋和不寻常的身体感觉。SA的长期影响是 通过观察表明，急性毒性体征和症状的强度可以预测 症状的严重性，在PBC积聚后发展，并在治疗后持续数月或数年。 这种情况说明迫切需要预防或治疗PBC对异常神经元的影响。 活动及其根本原因，但没有找到有效的解决办法。提出了本研究项目 旨在通过检测人体剂量的PBC对运动神经元的影响来满足这一需求 在体内研究的荷癌大鼠身上。该提案将三个具体目标列为最符合逻辑的AND 有效的下一步措施，所有这些都得到初步实验和发现的支持和证明是可行的。AIM 1将测试 中枢神经系统(CNS)内运动神经元胞体中PBC的蓄积是否必要 或足以诱发SA。对中枢神经系统的重视是该领域打破常规的一个新方向，但 未经检验的共识是，SA起源于不寻常的，即周围神经发出信号的异位部位 系统。这一新的方向是由最近和决定性的发现推动的，即汽车中的SA 神经元是在中枢神经系统内产生的。将使用以下方法测试SA的可能原因： 操纵PBC在运动神经元中的积聚。目标2将利用脊椎的特殊通道 运动神经元，用于在活体动物体内研究神经元变化的生物物理机制 兴奋性和自闭性。这一结果将首次提供关于PBC对内在兴奋性的影响的细节。 并将指导对运动神经元中其他神经元完全未知的影响的理解 中枢神经系统。目标3将测试运动神经元中SA由SA通过突触驱动的可能性，如下所示 感觉神经元。这种由PBC神经毒性引起的SA的系统检测将显著进展 通过批判性地评估三个具有很强循证潜力的主要候选机制 对急需制定的预防措施或治疗措施的影响。

Abstract The toxic effects of platinum-based compounds (PBCs) commonly used in chemotherapy weigh against their usefulness as the major option for successfully combating lethal cancers. The decision to opt for survival leaves people worldwide to suffer with PBC neurotoxicity that reduces quality of life by causing neurological disorders both during and long after treatment. Pain, strange sensations, fatigue, and difficulty with balance and walking are common symptoms, collectively known as chemotherapy-induced neuropathy (CIN). During treatment, both sensory and motor neurons are observed to fire unintentionally, i.e. they exhibit spontaneous firing (SA), and evidence suggests that SA bears responsibility for the earliest signs of distress, including uncontrolled muscle contraction, cramping, and unusual body sensations. Prolonged impact of SA is suggested by observations that the intensity of acute signs and symptoms of toxicity is predictive of the severity of symptoms that develop after with PBC accumulation and persist for months or years after treatment. This situation describes the urgent need for prevention or treatment of PBC effects on abnormal neuronal activity and its underlying causes, but no effective solution has been found. The research project proposed here is designed to meet this need by examining the effects of human-scaled doses of PBC on motor neurons in cancer-bearing rats studied in vivo. The proposal prioritizes three specific aims as the most logical and impactful next steps, all supported and proven feasible by preliminary experiments and findings. Aim 1 will test whether PBC accumulation in motor neuron cell bodies within the central nervous system (CNS) is necessary or sufficient to induce SA. Emphasis on the CNS is a new direction in the field that breaks with common, yet untested consensus that SA originates at unusual, i.e. ectopic sites of firing out in the peripheral nervous system. This new direction is driven by recent and conclusive findings presented here that SA in motor neurons is produced within the CNS. A possible cause of SA will be tested using methods to measure and manipulate PBC accumulation in motoneurons. Aim 2 will take advantage of the exceptional access of spinal motor neurons for studying, within a living animal, the biophysical mechanisms underlying changes in neuronal excitability and SA. The results will provide the first ever detail about the effects of PBC on intrinsic excitability of motor neurons and will guide understanding of effects that are entirely unknown for other neurons in the CNS. Aim 3 will test the possibility that SA in motor neurons is driven synaptically by SA shown here for sensory neurons. This systematic examination of SA induced by PBC neurotoxicity will significantly advance the field by critically assessing three major candidate mechanisms having strong potential for evidence-based impact on urgently needed development of preventative measures or treatments.