Thalamic infusions as a treatment of limbic epilepsy

丘脑输注治疗边缘叶癫痫

基本信息

批准号：
7821361
负责人：
EDWARD H BERTRAM
金额：
$ 18.75万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7821361
关键词：
Adverse effects Affect Affinity Anatomy Animal Model Area Behavior Behavioral Benchmarking Benzodiazepines Blood - brain barrier anatomy Brain Brain Part Brain region Cannulas Chronic Clinic Clinical Clinical Trials Cognitive Communities Complex Data Development Disease Dorsal Drug Delivery Systems Electronics Epilepsy Evolution Future GABA-A Receptor Goals Impaired cognition Individual Infusion procedures Intractable Epilepsy Laboratories Link Location Medial Medial Dorsal Nucleus Methods Midline Thalamic Nuclei Miniaturization Modeling National Institute of Neurological Disorders and Stroke Nervous system structure Patients Pharmaceutical Preparations Pharmacology Phenobarbital Play Poison Public Health Rattus Role Screening procedure Seizures Solutions Staging Stimulus Synapses System Techniques Technology Temporal Lobe Testing Thalamic Nuclei Thalamic structure Therapeutic Uncertainty base cost drug testing falls improved interest intervention effect novel strategies pre-clinical programs receptor research study therapeutic target therapy development therapy resistant zolpidem

项目摘要

There is an ongoing wide ranging search for new therapies for intractable epilepsy. Although drugs with a variety of mechanisms remain a significant focus of therapy development, the current evolution in technology has opened up new possibilities. Stimulation of several regions of the nervous system has attracted significant interest and this approach now includes recognition programs to detect seizures at any early stage and deliver a programmed stimulus to break the seizure. This development has been made possible in part by the progressive miniaturization of electronics. A potential advantage of this approach is that therapy is delivered to a single area of the brain, a technique that may avoid the side effects that can come from the systemic administration of a drug that goes to all parts of the brain. Delivery of a drug to a single point has often been considered and has been shown to have effect in some animal models of seizures, and such therapy targeted to a specific region is one of the NINDS benchmarks for treating epilepsy. However, a practical and reliable method for preclinical screening and a means for chronic delivery have not been available. Recently we have been examining the potential role of the medial dorsal region of the thalamus in limbic seizures and have evidence that suggests that this area may represent a key point in the initial seizure circuit. In this project we will be testing the overall hypothesis that drug infusion into the medial dorsal thalamic nucleus will control spontaneous limbic seizures without significant behavioral side effects. To test this hypothesis we will use a rat model of limbic epilepsy with spontaneous seizures and infuse drugs into the medial dorsal region of the thalamus and determine the effects of this intervention on spontaneous seizures. In the course of this project we will define optimal targets and drugs. Because the issue of cognitive impairment as a consequence of any epilepsy treatment is a concern, we will also determine whether successful treatment with regard to seizure suppression also affects complex behaviors. At the end of this project we will have determined whether the approach of intracerebral drug infusion into a specific region has potential for clinical development by suppressing seizures with no clear cognitive cost. Moving the results of this study to the clinic will be facilitated by the presence of technology for long term continuous drug infusions into the CNS. Finally, if successful we will also have created a technique with which we might identify other, less toxic compounds that may be more effective than the ones tested in this study with less behavior cost.

正在进行的广泛搜索对顽固性癫痫的新疗法。尽管具有多种机制的药物仍然是治疗开发的重要重点，但技术的发展开发了新的可能性。刺激神经系统的几个区域引起了极大的兴趣，这种方法现在包括在任何早期阶段检测癫痫发作的识别计划，并提供了编程的刺激以打破癫痫发作。这一发展是由于电子产品的进行性小型化而成为可能的。这种方法的一个潜在优势是将治疗递送到大脑的单个区域，该技术可能避免从系统地给予大脑各个部位的药物的系统给药带来的副作用。经常考虑将药物递送到单点，并已被证明在某些癫痫发作的动物模型中具有作用，而针对特定区域的这种治疗是用于治疗癫痫的NINDS基准之一。但是，尚无一种实用可靠的临床前筛查方法和一种长期分娩的手段。最近，我们一直在研究丘脑在边缘癫痫发作中的内侧背区域的潜在作用，并有证据表明该区域可能代表初始癫痫发作中的关键点。在这个项目中，我们将测试一个总体假设，即药物输注内侧丘脑核将控制自发的边缘癫痫发作，而没有明显的行为副作用。为了检验这一假设，我们将使用自发癫痫发作的边缘癫痫大鼠模型，并注入丘脑的背侧区域，并确定这种干预对自发癫痫发作的影响。在这个项目的过程中，我们将定义最佳目标和药物。由于因任何癫痫治疗而导致的认知障碍问题问题是一个问题，因此我们还将确定在癫痫发作抑制方面的成功治疗是否也会影响复杂的行为。在该项目结束时，我们将确定脑内药物输注到特定区域的方法是否通过抑制癫痫发作而没有明显的认知成本来实现临床发育。将这项研究的结果转移到诊所将通过长期连续药物输注中枢神经系统的技术的存在来促进。最后，如果成功的话，我们还将创建一种技术，我们可以识别其他毒性化合物，这些化合物可能比本研究中测试的技术更有效，而行为成本较小。