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Ampakines and Respiratory Neuroplasticity

安帕金和呼吸神经可塑性

基本信息

批准号：
10213119
负责人：
DAVID D FULLER
金额：
$ 37.35万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213119
关键词：
AMPA Receptors Acids Acute Area Brain Stem Breathing Cell model Cervical Cervical spinal cord injury Chronic Clinical Data Dose Effectiveness Evaluation Florida Foundations Glutamates Human Hypercapnic respiratory failure Hypoxia Impairment Intravenous Kinetics Mediating Methods Modality Modeling Morbidity - disease rate Motor Motor Neurons Motor Pathways Motor output Neuronal Plasticity Outcome Measure Output Pathway interactions Patients Pharmaceutical Preparations Pharmacology Rattus Receptor Activation Recovery of Function Rehabilitation therapy Research Respiration Disorders Respiratory Muscles Respiratory Stimulants Respiratory physiology Rodent Safety Series Serotonin Serotonin Agonists Serotonin Antagonists Signal Pathway Signaling Molecule Site Small Interfering RNA Spinal Spinal Cord Spinal cord injury Structure of phrenic nerve Synapses Synaptic Transmission Synaptic plasticity Testing Tidal Volume Time Universities Work authority awake base evidence base experience experimental study improved innovation mortality motor disorder motor function improvement motor impairment neurochemistry neurological rehabilitation neurophysiology relating to nervous system respiratory serotonin receptor ventilation

项目摘要

ABSTRACT Respiratory-related motor dysfunction is the leading cause of morbidity and mortality following cervical spinal cord injury (SCI). Respiratory impairments largely reflect impaired bulbospinal glutamatergic synaptic transmission to spinal respiratory motoneurons. Ampakines are allosteric modulators of α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor channel kinetics that enhance glutamatergic synaptic transmission. Since glutamatergic bulbospinal excitation of spinal respiratory motoneurons is driven in part by motoneuron AMPA receptor activation, enhancing spinal AMPA-mediated synaptic currents could increase motoneuron output. The central hypothesis guiding this proposal is that ampakines are an effective pharmacologic approach to improve breathing function after incomplete cervical SCI. Aim 1 will test the hypothesis that acute delivery of ampakines stimulates breathing after incomplete cervical SCI, and does so by facilitating synaptic transmission in spared respiratory motor pathways in the spinal cord. These experiments will determine effective dose, safety profile and primary site of action (e.g., medullary vs. spinal). Studies will be done after both acute and chronic cervical SCI; minute ventilation and respiratory muscle electromyogram (EMG) activity will be evaluated in unanesthetized rats; phrenic nerve activity will be evaluated in anesthetized rats. Aim 2 moves beyond direct stimulation of breathing to test the hypothesis that ampakines increase the capacity for neuroplasticity in the phrenic motor circuit. Preliminary data indicate that ampakine pre-treatment greatly enhances phrenic motor plasticity induced by spinal, serotonin receptor agonist administration. Based on these data, we propose a detailed cellular model to explain the impact of ampakines on serotonin- dependent phrenic motor plasticity. Additional preliminary data show that ampakine pretreatment causes dramatic increases in phrenic motor facilitation induced by acute intermittent hypoxia (AIH). We focus on AIH since it is well-established to induce spinal, serotonin-dependent phrenic motor plasticity, and has proven to be a simple and safe neurorehabilitation approach in humans with SCI. Thus, low-dose ampakines may be useful to enhance the impact of other neurorehabilitation modalities. Hypotheses derived from the cellular model will be tested by cervical spinal delivery of serotonin receptor antagonists and/or siRNAs targeting downstream signaling molecules. A comprehensive series of outcome measures will include neurophysiological studies of phrenic output, neurochemical evaluation of signaling pathways, and assessment of respiratory capacity in awake rats. We suggest that the proposed work is significant because of the need for strategies to improve motor function in patients with SCI. Innovative aspects include: 1) the use of ampakines to stimulate breathing after cervical SCI; 2) the use of ampakines increase respiratory neuroplasticity and functional recovery, and 3) the first cellular model to explain the impact of ampakines on spinal respiratory neuroplasticity.

摘要呼吸相关的运动功能障碍是颈椎病术后发病和死亡的主要原因脊髓损伤（SCI）。呼吸障碍主要反映了受损的球脊髓神经元能突触传递到脊髓呼吸运动神经元。Ampakines是α-氨基-3-羟基-5-羟基-β-氨基丁酸的变构调节剂。甲基-4-异恶唑丙酸（AMPA）受体通道动力学增强多巴胺能突触传输由于脊髓呼吸运动神经元的延髓脊髓兴奋部分是由运动神经元AMPA受体激活，增强脊髓AMPA介导的突触电流，可增加运动神经元输出指导这一建议的中心假设是，ampakines是有效的改善不完全性颈脊髓损伤后呼吸功能的药理学方法。目标1将测试假设急性给予ampakines刺激不完全颈脊髓损伤后的呼吸，促进脊髓中备用呼吸运动通路中的突触传递。这些实验将确定有效剂量、安全性特征和主要作用部位（例如，髓对脊髓）。研究将急性和慢性颈脊髓损伤后进行;分钟通气量和呼吸肌肌电图 (EMG)将在未麻醉的大鼠中评价膈神经活性;将在麻醉的大鼠中评价膈神经活性。大鼠目的2超越了直接刺激呼吸，以测试ampakines增加呼吸的假设。膈神经运动回路中神经可塑性的能力。初步数据表明，安巴金预处理大大增强了由脊髓5-羟色胺受体激动剂给药诱导的膈运动可塑性。基于根据这些数据，我们提出了一个详细的细胞模型来解释ampakines对5-羟色胺的影响- 依赖性膈运动可塑性额外的初步数据显示，安巴金预处理导致急性间歇性缺氧（AIH）诱导的膈运动易化显著增加。我们专注于AIH 因为它已被公认诱导脊髓、降钙素依赖性膈运动可塑性，并已被证明一种简单而安全的SCI患者神经康复方法。因此，低剂量的安帕金可能是有用的，以增强其他神经康复方式的影响。从细胞模型推导出的假设将通过颈脊髓递送5-羟色胺受体拮抗剂和/或靶向下游的siRNA进行测试信号分子一系列全面的结果测量将包括神经生理学研究，膈输出量、信号传导通路的神经化学评价和呼吸能力评估，清醒的老鼠我们认为，拟议的工作是重要的，因为需要战略，以改善 SCI患者的运动功能。创新方面包括：1）使用ampakines刺激呼吸 2）ampakines的使用增加了呼吸神经可塑性和功能恢复，以及3）第一个解释ampakines对脊髓呼吸神经可塑性影响的细胞模型。