Efficacy of Necrostatins on Posttraumatic Epilepsy

坏死他汀对创伤后癫痫的疗效

基本信息

批准号：
7937833
负责人：
W Dalton Dietrich
金额：
$ 40.38万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
2009-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7937833
关键词：
Acute Address Affect Animal Model Animals Antiepileptic Agents Apoptosis Area Attenuated Behavioral Biochemical Biological Preservation Blood Blood - brain barrier anatomy Brain Injuries Brain region Caspase Cause of Death Cell Death Cell Survival Cells Cerebral cortex Characteristics Clinical Research Cognition Cognitive Contusions Cultured Cells Data Dose Drug Kinetics Epilepsy Experimental Models External Capsule Functional disorder Future Grant Health Hippocampus (Brain)Histopathology Human Impaired cognition Incidence Inflammation Infusion procedures Injury Intravenous infusion procedures Ischemia Laboratories Lead Learning Liquid substance Medical Memory Metabolism Modeling Molecular Molecular Target Monitor Mus Necrosis Neurons Outcome Measure Pathogenesis Pathology Pathway interactions Patients Pentylenetetrazole Percussion Pharmacological Treatment Pharmacotherapy Phase Phosphotransferases Population Property Protein Kinase Publishing Rattus Regulation Reporting Research Research Personnel Research Proposals Seizures Signal Transduction Testing Therapeutic Tissue Sample Tissues Translational Research Trauma Traumatic Brain Injury United States Vascular Permeabilities Work absorption brain tissue cell injury cell type clinically relevant cognitive function cost disability experience functional outcomes human RIPK1 protein improved improved functioning inhibitor/antagonist intravenous administration nervous system disorder neuroprotection novel novel therapeutic intervention pharmacokinetic model preclinical study programs response small molecule small molecule libraries tool white matter white matter damage

项目摘要

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15- NS-103: Demonstration of "Proof of Concept" for a New Therapeutic Approach in a Neurological Disease. Traumatic brain injury (TBI) is a significant health concern, affecting approximately 1.4 million people in the United States each year at a cost of $56 billion. Although significant research has been conducted to understand the pathophysiology of TBI, no pharmacological therapies are currently available to victims suffering from TBI. Posttraumatic epilepsy (PTE) occurs in over 30% of patients with moderate or severe TBI. Recent studies have implicated a novel injury mechanism identified as programmed necrosis (necroptosis) that merits consideration as a target for pharmacotherapy after TBI. Recently, a first in class small molecule inhibitor of necroptosis, TL14077 has been identified. We propose to evaluate the neuroprotective and anti- epileptic properties of this compound in a clinically relevant model of TBI. Recent work in our laboratory has shown that moderate fluid percussion (FP) brain injury reduces the threshold for seizures documented by both behavioral as well as electrophysiological changes when the convulsive agent PTZ is given to posttraumatic rats. Also, published findings reported that moderate TBI leads to long term alterations in sensorimotor as well as cognitive function. Thus, we hypothesize that treatment with an anti-necroptosis molecule (TL14077) will reduce the histopathological as well as functional consequences of this traumatic insult. In Aim 1, we will evaluate and optimize the dose-response efficacy and pharmokinetics of TL14077 by intravascular infusion. While previous studies have shown that this small molecule crosses the blood-brain barrier, pharmokinetic studies to document absorption, distribution, metabolism and elimination are required prior to the treatment studies. In Specific Aim 2, we will determine mechanisms by which inhibitors of necroptosis alter molecular mechanisms of traumatic injury in this model. Specifically, we will assess whether treatment with TL14077 will inhibit trauma-induced activation of receptor-interacting protein kinase 1 (RIPK1) activity in vulnerable brain regions. In Aim 3, we will assess the histopathological and cognitive consequences of TL14077 treatment following moderate FP brain injury. For these studies, histopathological characterization of contusion volume, selective neuronal damage, white matter pathology along with behavioral outcome measures including cognition will be evaluated. Finally, in Aim 4, the effects of TL14077 on PTE will be investigated. Seizure activity will be monitored by behavioral and electrophysiological indicators of neuronal excitation. The proposed studies are supported by investigators and medical professionals with expertise using the various experimental tools and outcome measures necessary to expand our repertoire of therapies available to patients suffering from TBI. Importantly, these preclinical studies could provide necessary data to initiate Phase I clinical studies in the near future targeting acute TBI in humans. Traumatic brain injury (TBI) is a major cause of death and disability in the United States. There are currently no treatments to reverse the behavioral consequences of brain trauma. This grant will test whether a novel compound targeting a relatively new pathway of cell death after trauma will reduce the incidence of epilepsy and improve functional outcome in a clinically relevant animal model of TBI.

描述（由申请人提供）：该申请涉及广泛的挑战领域（15）转化科学和特定挑战主题，15- NS-103：在神经系统疾病中采用新的治疗方法的“概念证明”。创伤性脑损伤（TBI）是一个重大的健康问题，每年影响美国约140万人，耗资560亿美元。尽管已经进行了大量研究以了解TBI的病理生理学，但目前尚无TBI的受害者使用药理疗法。超过30％的中度或重度TBI患者发生创伤后癫痫（PTE）。最近的研究暗示了一种新型的损伤机制，被确定为程序性坏死（坏死），该机制值得考虑作为TBI后药物治疗的靶标。最近，已经鉴定出了第一个类小分子的小分子抑制剂TL14077。我们建议在TBI的临床相关模型中评估该化合物的神经保护性和抗癫痫特性。我们实验室中的最新工作表明，当抽搐剂PTZ赋予创伤后大鼠时，中等液体打击乐（FP）脑损伤降低了行为和电生理学变化的癫痫发作的阈值。此外，已发表的发现报道说，中等TBI导致感觉运动和认知功能的长期改变。因此，我们假设用抗肿瘤分子（TL14077）治疗将减少这种创伤性侮辱的组织病理学以及功能后果。在AIM 1中，我们将通过血管内输注评估和优化TL14077的剂量反应功效和药理。虽然先前的研究表明，这个小分子跨越了血脑屏障，但在治疗研究之前需要进行药物动力学研究以记录吸收，分布，代谢和消除。在特定的目标2中，我们将确定在该模型中坏死性抑制剂改变创伤性损伤的分子机制的机制。具体而言，我们将评估TL14077的治疗是否会抑制创伤引起的受体相互作用蛋白激酶1（RIPK1）活性在脆弱的大脑区域的活性。在AIM 3中，我们将评估中度FP脑损伤后TL14077治疗的组织病理学和认知后果。对于这些研究，将评估挫伤量，选择性神经元损害，白质病理学以及包括认知在内的行为结果指标的组织病理学表征。最后，在AIM 4中，将研究TL14077对PTE的影响。癫痫活性将通过神经元激发的行为和电生理指标来监测。提出的研究得到了研究人员和医疗专业人员的支持，并使用各种实验工具和结果指标进行了专业知识，以扩大我们可用于患有TBI的患者可用的疗法库。重要的是，这些临床前研究可以提供必要的数据来启动不久的将来针对人类急性TBI的I期临床研究。创伤性脑损伤（TBI）是美国死亡和残疾的主要原因。目前尚无治疗方法来扭转脑创伤的行为后果。该赠款将测试针对创伤后细胞死亡途径的新型化合物是否会减少癫痫的发生率并改善TBI临床相关动物模型中的功能结果。