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.

抽象的 在化学疗法中常用的铂基化合物（PBC）的毒性作用与其 作为成功打击致命癌症的主要选择，有用。选择生存的决定 让全世界的人们患有PBC神经毒性，从而通过导致神经系统来降低生活质量 治疗期间和长期疾病。痛苦，奇怪的感觉，疲劳和平衡困难 步行是常见的症状，统称为化学疗法诱导的神经病（CIN）。期间 治疗，感官和运动神经元都无意中发射，即它们自发发射 解雇（SA）和证据表明，SA承担着最早的困扰迹象，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 通过观察到急性体征和毒性症状的强度的建议是预测 PBC积累并在治疗后数月或数年持续存在的症状严重程度。 这种情况描述了预防或治疗PBC对异常神经元影响的迫切需要 活动及其根本原因，但尚未找到有效的解决方案。研究项目提出了 这里旨在通过检查人体量剂量的PBC对运动神经元的影响来满足这种需求 在体内研究的癌症大鼠中。该提案将三个具体目标优先为最合乎逻辑，并且 有影响力的下一步，所有初步实验和发现都得到了支持和证明。 AIM 1将测试 中枢神经系统内的运动神经元细胞体中的PBC是否积累是必要的 或足以诱导SA。强调中枢神经系统是该领域的一个新方向，它与共同点破裂，但 SA起源于不寻常的未经测试的共识，即在周围神经中发射的异位部位 系统。这个新的方向是由在这里提出的最新和结论性的发现驱动的 神经元在中枢神经系统内产生。 SA的可能原因将使用测量方法进行测试和 在运动神经元中操纵PBC积累。 AIM 2将利用脊柱的特殊获取 运动神经元用于研究活性动物，是神经元变化的生物物理机制 兴奋性和SA。结果将提供有关PBC对固有兴奋性影响的第一个细节 运动神经元，并将指导对其他神经元完全未知的影响的理解 CNS。 AIM 3将测试运动神经元中的SA在此处显示的SA驱动的可能性 感觉神经元。 PBC神经毒性引起的SA的系统检查将显着提高 通过批判性评估具有强大潜力的循证潜力的三种主要候选机制，该领域 对迫切需要开发预防措施或治疗的影响。