Mechanisms underlying spontaneous firing by motoneurons with acute neurotoxicity

具有急性神经毒性的运动神经元自发放电的机制

• 批准号: 10570842
• 负责人: Timothy C Cope
• 金额: $ 48.49万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-11 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570842
• 关键词: Action Potentials; Acute; Afferent Neurons; Aftercare; Animals; Axon; Biophysical Process; Biophysics; Blood - brain barrier anatomy; Cancer Survivor; Central Nervous System; Chemotherapy-Oncologic Procedure; Chronic; Cimetidine; Cisplatin; Clinical; Clinical Trials; Closure by clamp; Consensus; Data; Development; Distress; Dose; Dysesthesias; Electrophysiology (science); Equilibrium; Esthesia; Exclusion; Exhibits; Fatigue; Fire - disasters; Functional disorder; Human; Infiltration; Ion Channel; Knowledge; Lidocaine; Life; Malignant Neoplasms; Measures; Methods; Modeling; Motor Neurons; Movement Disorders; Muscle; Muscle Contraction; Muscle Cramp; Muscle fasciculation; Nervous System; Neurons; Outcome; Pain; Patients; Peripheral; Peripheral Nervous System; Persons; Platinum; Prevention; Preventive measure; Preventive treatment; Property; Quality of life; Rattus; Research Project Grants; Sensory; Severities; Signs and Symptoms; Site; Spasm; Spinal; Spinal Ganglia; Symptoms; Synapses; Testing; Thinking; Toxic effect; Vertebral column; Voltage-Clamp Technics; Walking; acute symptom; biophysical analysis; bodily sensation; channel blockers; chemotherapy; chemotherapy induced neuropathy; common symptom; design; disability; evidence base; experimental study; extracellular; immunoreactivity; in vivo; inhibitor; meetings; nervous system disorder; neural; neuronal cell body; neuronal excitability; neurotoxic; neurotoxicity; novel; oxaliplatin; pre-clinical; preclinical study; prevent; response; somatosensory; spinal nerve posterior root; success; symptom treatment; treatment effect

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.

摘要 化疗中常用的铂基化合物（PBMC）的毒性作用与其毒性作用相反。 作为成功对抗致命癌症的主要选择的有用性。选择生存的决定 使世界各地的人们遭受PBC神经毒性，通过引起神经系统疾病而降低生活质量。 在治疗期间和治疗后很长时间内都有障碍。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变（CIN）。期间 在治疗中，观察到感觉神经元和运动神经元都无意地放电，即它们表现出自发放电。 射击（SA），有证据表明，SA承担责任的最早迹象的痛苦，包括 不受控制的肌肉收缩、痉挛和不寻常的身体感觉。SA的长期影响是 观察结果表明，急性体征和毒性症状的强度可预测 PBC累积后出现的症状的严重程度，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，但没有找到有效的解决办法。 本文旨在通过研究人体比例剂量的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。该提案将三个具体目标列为最符合逻辑的优先事项， 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和证明是可行的。目标1将测试 PBC在中枢神经系统（CNS）内运动神经元细胞体中的蓄积是否是必要的 或足以诱发SA。强调中枢神经系统是该领域的一个新方向， 未经检验的共识，即SA起源于不寻常的，即在外周神经放电的异位部位 系统这一新的方向是由最近的和结论性的发现驱动的，在这里，SA在运动 神经元在CNS内产生。SA的可能原因将使用测量方法进行测试， 操纵PBC在运动神经元中的积聚。目标2将利用特殊的脊柱入路 运动神经元的研究，在活的动物，生物物理机制的变化，神经元 兴奋性和SA。该结果将首次提供PBC对内在兴奋性影响的详细信息 运动神经元，并将指导理解的影响，是完全未知的其他神经元在 CNS。目标3将测试运动神经元中的SA由此处所示的SA突触驱动的可能性， 感觉神经元对PBC神经毒性引起SA的系统研究，将为PBC神经毒性的研究提供新的思路 通过严格评估三个主要的候选机制， 对迫切需要的预防措施或治疗方法的发展产生影响。