Mechanisms underlying spontaneous firing by motoneurons with acute neurotoxicity

摘要 化疗中常用的铂基化合物 (PBC) 的毒性作用与它们的作用相权衡。 作为成功对抗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，这种毒性会导致神经系统疾病，从而降低生活质量 治疗期间和治疗后很长时间内出现疾病。疼痛、奇怪的感觉、疲劳和平衡困难 行走是常见症状，统称为化疗引起的神经病变（CIN）。期间 在治疗中，感觉神经元和运动神经元都被观察到无意中放电，即它们表现出自发性 解雇（SA），并且有证据表明 SA 对最早的遇险迹象负有责任，包括 不受控制的肌肉收缩、痉挛和异常的身体感觉。 SA 的长期影响是 观察表明，急性毒性体征和症状的强度可以预测 PBC 积聚后出现的症状严重程度，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，但尚未找到有效的解决方案。提出的研究项目 这里旨在通过检查人体剂量的 PBC 对运动神经元的影响来满足这一需求 在荷癌大鼠体内进行研究。该提案优先考虑了三个最合乎逻辑且最具体的目标 有影响力的后续步骤，所有这些都得到了初步实验和发现的支持并证明是可行的。目标 1 将进行测试 PBC 在中枢神经系统 (CNS) 内的运动神经元细胞体中的积累是否是必要的 或足以诱发SA。强调中枢神经系统是该领域打破常规的新方向 未经检验的共识认为 SA 起源于不寻常的地方，即周围神经的异位放电部位 系统。这一新方向是由本文提出的最新结论性发现推动的，即电机中的 SA 神经元是在中枢神经系统内产生的。 SA 的可能原因将使用测量和测量方法进行测试 操纵运动神经元中的 PBC 积累。目标 2 将利用脊柱的特殊通道 运动神经元，用于在活体动物中研究神经元变化背后的生物物理机制 兴奋性和SA。结果将首次提供有关 PBC 对内在兴奋性影响的详细信息 运动神经元的研究，并将指导理解运动神经元中其他神经元完全未知的效应 中枢神经系统。目标 3 将测试运动神经元中的 SA 由此处显示的 SA 突触驱动的可能性 感觉神经元。对 PBC 神经毒性引起的 SA 的系统检查将显着推进 通过严格评估具有强大循证潜力的三个主要候选机制 对迫切需要制定的预防措施或治疗方法的影响。

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.