Progressive seizure-induced cardiorespiratory dysfunction in a novel mutant rat model of seizure disorder

新型癫痫病突变大鼠模型中进行性癫痫发作引起的心肺功能障碍

基本信息

批准号：
10630066
负责人：
Matthew Robert Hodges
金额：
$ 58.06万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-17 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630066
关键词：
Acute Address Adenosine Affect Animal Model Anti-Inflammatory Agents Antibodies Antiepileptic Agents Apnea Astrocytes Blood Pressure Brain Brain Stem Breathing Cause of Death Cell Death Cell Nucleus Cell physiology Cells Cessation of life Chronic Cicatrix Data Electroencephalography Epilepsy Event Exposure to Failure Female Fluoxetine Functional disorder Genes Glial Fibrillary Acidic Protein Goals Heart Arrest Heart Rate Human Hypoxia Impairment Inflammation Inflammatory Interleukin-1 Interleukin-10 Interleukins Intervention Intractable Epilepsy Knowledge Lead Mediating Mediator Membrane Potentials Microglia Modeling Molecular Mutation Neuromodulator Neuronal Plasticity Neurons Nuclear RNA Outcome Pathologic Pathology Pathway interactions Patients Pattern Persons Phenotype Potassium Channel Rattus Recurrence Reflex action Reproducibility Risk Seizures Selective Serotonin Reuptake Inhibitor Serotonergic System Serotonin Signal Pathway Signal Transduction Site Stereotyping System Technology Testing Therapeutic Intervention Time Tissue-Specific Gene Expression Tissues Tonic - clonic seizures audiogenic seizure cohort epileptiform glial activation high risk improved outcome insight inward rectifier potassium channel male mortality mutant negative affect nervous system disorder neural circuit neural network neuroinflammation neuroregulation new therapeutic target novel novel therapeutics nucleus ambiguus pharmacologic pre-clinical preBotzinger complex prevent receptor respiratory response risk mitigation sound sudden unexpected death in epilepsy therapeutic target transcriptome sequencing ventilation

Acute Address Adenosine Affect Animal Model Anti-Inflammatory Agents Antibodies Antiepileptic Agents Apnea Astrocytes Blood Pressure Brain Brain Stem Breathing Cause of Death Cell Death Cell Nucleus Cell physiology Cells Cessation of life Chronic Cicatrix Data Electroencephalography Epilepsy Event Exposure to Failure Female Fluoxetine Functional disorder Genes Glial Fibrillary Acidic Protein Goals Heart Arrest Heart Rate Human Hypoxia Impairment Inflammation Inflammatory Interleukin-1 Interleukin-10 Interleukins Intervention Intractable Epilepsy Knowledge Lead Mediating Mediator Membrane Potentials Microglia Modeling Molecular Mutation Neuromodulator Neuronal Plasticity Neurons Nuclear RNA Outcome Pathologic Pathology Pathway interactions Patients Pattern Persons Phenotype Potassium Channel Rattus Recurrence Reflex action Reproducibility Risk Seizures Selective Serotonin Reuptake Inhibitor Serotonergic System Serotonin Signal Pathway Signal Transduction Site Stereotyping System Technology Testing Therapeutic Intervention Time Tissue-Specific Gene Expression Tissues Tonic - clonic seizures audiogenic seizure cohort epileptiform glial activation high risk improved outcome insight inward rectifier potassium channel male mortality mutant negative affect nervous system disorder neural circuit neural network neuroinflammation neuroregulation new therapeutic target novel novel therapeutics nucleus ambiguus pharmacologic pre-clinical preBotzinger complex prevent receptor respiratory response risk mitigation sound sudden unexpected death in epilepsy therapeutic target transcriptome sequencing ventilation

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项目摘要

Project Summary More than 50 million people suffer from epilepsy globally. Current anti-epileptic drugs (AEDs) cannot prevent seizures in ~30% of these patients, leading to uncontrolled or refractory epilepsy. Unfortunately, these patients are at extreme risk of Sudden Unexpected Death in Epilepsy (SUDEP), which is the leading cause of death in this cohort. Based on landmark SUDEP studies, the current hypothesis is that recurrent seizures induce extreme cardiorespiratory suppression and/or failure through negative effects on the neural networks that regulate vital functions such as breathing, heart rate and blood pressure. However, it remains unclear how repeated seizures fundamentally affect cardiorespiratory control networks within the brainstem, and by what mechanisms these vital systems fail in SUDEP. Here we aim to characterize the pathophysiologic consequences of repeated seizures in a novel rat model with a known mutation in a potassium channel gene (kcnj16; SSkcnj16-/- rats), in which a specific sound of mild intensity readily and reproducibly causes generalized tonic-clonic seizures (GTCSs). Sound-induced GTCSs in SSkcnj16-/- rats led to a stereotypic pattern of events similar to that described in epilepsy patients, including post-ictal generalized EEG suppression and apnea, followed by respiratory rate (RR) and heart rate (HR) suppression. Repeated seizures (1/day for up to 10 days) led to: 1) augmented post- ictal suppression of RR and HR, reduced ventilatory responses to hypoxic and hypercapnic challenges, and unexpected mortality in ~33% of these rats. Brainstem tissue analyses of SSkcnj16-/- rats exposed to repeated seizures showed evidence of time-dependent increases in inflammation and dysregulation of adenosine (ADO) and serotonin (5-HT) – two powerful modulators of cardiorespiratory neural networks. Finally, pharmacologically augmenting 5-HT with an SSRI (fluoxetine) prevented the progressive suppression of post-ictal RR with repeated seizures. Herein we will test our central hypothesis that repeated seizures cause a progressive brainstem pathology initiated by neuroinflammation and mediated by ADO and 5-HT dysfunction leading to cardiorespiratory suppression and/or failure in SUDEP. The proposed studies utilizing this novel mutant rat model will provide: 1) a comprehensive characterization of the progressive pathophysiological responses to repeated audiogenic seizures, and sequence of events leading to unexpected death (Aim 1), 2) identified mechanisms of dysfunction in inflammatory and/or neuromodulatory pathways within critical cardiorespiratory brainstem nuclei negatively affected by repeated seizures (Aim 2), and 3) interventions that functionally test our hypothesis by blocking neuroinflammation or modulating ADO or 5-HT system activity on the backdrop of repeated seizures (Aim 3). We will utilize a combination of established and cutting-edge technologies to provide unprecedented molecular, cellular and systems-level insights into the pathophysiological consequences repeated seizures on vital control systems in order to identify novel targets for therapeutic interventions aimed at preventing or mitigating the risk of SUDEP in human epilepsy patients.

项目摘要全球有超过5000万人患有癫痫病。当前的抗癫痫药（AED）无法阻止这些患者中约有30％的癫痫发作导致不受控制或难治性癫痫。不幸的是，这些患者处于癫痫（SUDEP）突然意外死亡的极端风险，这是死亡的主要原因这个队列。基于具有里程碑意义的SUDEP研究，当前的假设是复发性癫痫发作会影响极端通过对调节重要的神经网络的负面影响，心肺抑制和/或失败呼吸，心率和血压等功能。但是，尚不清楚如何重复癫痫发作从根本上影响脑干内的心肺控制网络，以及这些机制重要系统在SUDEP中失败。在这里，我们旨在表征重复的病理生理后果在钾通道基因（KCNJ16; SSKCNJ16 - / - 大鼠）中具有已知突变的新型大鼠模型中的癫痫发作，在轻度强度的特定声音很容易且可重复地引起广义的强调持续性癫痫发作（GTCSS）。 SSKCNJ16 - / - 大鼠中的声音引起的GTCS导致了类似于描述的事件的刻板印象模式在癫痫患者中，包括截肢后全身性脑力抑制和呼吸暂停，随后是呼吸率（RR）和心率（HR）抑制。重复癫痫发作（最多1天，最多10天）导致：1）增强后 - ICTAR抑制RR和HR，降低对低氧和过度碳水化合物挑战的通气反应以及这些大鼠中约有33％的意外死亡率。 SSKCNJ16 - / - 大鼠的脑干组织分析暴露于重复癫痫发作显示腺苷炎症和失调（ADO）的时间依赖性增加的证据和5-羟色胺（5-HT） - 两个强大的心肺神经网络的调节剂。最后，在药品上用SSRI（Fluoxetine）增强5-HT，以防止重复逐渐抑制后Ictal RR 癫痫发作。在此，我们将测试我们的中心假设，即重复癫痫发作会引起脑干由神经炎症引发的病理学，并由ADO和5-HT功能障碍介导 SUDEP中的心肺抑制和/或失败。提出的使用这种新型突变大鼠的研究模型将提供：1）对进行性病理生理反应的全面表征重复的听力癫痫发作和导致意外死亡的事件的顺序（目标1），2）确定关键心肺内炎症和/或神经调节途径中功能障碍的机制脑干核对反复发作的负面影响（AIM 2）和3）在功能上测试我们的干预措施通过阻止神经炎症或调节ADO或5-HT系统活动的假设重复癫痫发作（目标3）。我们将利用已建立和尖端技术的组合来提供对病理生理后果的前所未有的分子，细胞和系统级别的见解重复对重要控制系统的癫痫发作，以确定针对治疗干预措施的新目标预防或减轻人类癫痫患者SUDEP的风险。