Chronic TBI Bcl 2-20:34 Protection Against Lowered Seizure Susceptibility

慢性 TBI Bcl 2-20:34 预防癫痫易感性降低

• 批准号: 8696752
• 负责人: ROI Ann WALLIS
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696752
• 关键词: Acute; Adult; American; BCL-2 Protein; BCL2 gene; Behavioral; Biochemical; Biomechanics; Brain; Brain Injuries; Cause of Death; Cell Nucleus; Cells; Charge; Chronic; Complication; Craniocerebral Trauma; Development; Epilepsy; Experimental Models; Generations; Healthcare; Hippocampus (Brain); In Vitro; Injection of therapeutic agent; Injury; Lateral; Lead; Learning; Left; Life; Long-Term Potentiation; Longevity; Magnesium; Membrane; Memory; Memory Loss; Mitochondria; Mitochondrial Swelling; Modeling; Morbidity - disease rate; Neurons; Pathologic; Pathway interactions; Patients; Peptides; Perforant Pathway; Persons; Physiologic pulse; Physiological; Picrotoxin; Play; Post-Traumatic Epilepsy; Predisposition; Production; Protein Binding; Psychosocial Influences; Pyramidal Cells; Rattus; Reactive Oxygen Species; Recurrence; Regulation; Respiration; Risk; Role; Seizures; Site; Slice; Societies; Structure; Sudden Death; Survivors; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Time; Trauma; Traumatic Brain Injury; Veterans; brain cell; combat; controlled cortical impact; dentate gyrus; granule cell; hippocampal cell loss; hippocampal subregions; improved; in vivo; injured; male; mortality; outcome forecast; prevent; research study; treatment strategy

DESCRIPTION (provided by applicant): Traumatic Brain Injury (TBI) is a frequent combat injury. Unfortunately, survivors of head trauma may go on later to develop recurrent seizures. This problem, termed post-traumatic epilepsy, is associated with significant morbidity and mortality. The most common form of post-traumatic epilepsy originates in the hippocampus of the temporal lobe. Up to one third of such patients have medically intractable post- traumatic epilepsy. As such they are at risk for a number of complications including sudden death, physical injuries, memory loss and a host of psychosocial issues. Due to this problem, a call has been made by the American Epilepsy Society for chronic studies of post-traumatic epilepsy. Therefore, we have tailored our proposal to provide information for this need. In our preliminary studies, we have used a model of TBI called controlled cortical impact (CCI) in adult male rats and found that seizure threshold is not only decreased after CCI, but continues to decline for at least 6 months thereafter. At this time we propose to evaluate seizure threshold chronically after lateral CCI over the life-span of the adult rat, which is about 24 months. During that time, we plan to perform electrophysiological, histological and biochemical experiments in vitro and in vivo techniques to evaluate seizure threshold in hippocampal subregions, including the dentate, CA3 and CA1 every 6 months after CCI. We have also found in our preliminary studies, evidence that treatment with the Bcl-220-34 peptide may prevent the lowering of seizure threshold after CCI. Therefore, we will also evaluate this treatment strategy in our proposal. In addition, we will examine a potential mechanism of action for the Bcl-220-34 peptide, which may indicate mitochondrial involvement in the generation of lowered seizure threshold after TBI. To this end, we will also evaluate mitochondrial structure and function after CCI with and without treatment with the Bcl-220-34 peptide.

描述（由申请人提供）： 创伤性脑损伤（TBI）是一种常见的战斗损伤。不幸的是，头部创伤的幸存者可能会在以后发展为复发性癫痫。这个问题，被称为创伤后癫痫，是与显着的发病率和死亡率。最常见的创伤后癫痫起源于颞叶的海马体。多达三分之一的此类患者患有医学上难以治愈的创伤后癫痫。因此，他们面临着许多并发症的风险，包括猝死、身体伤害、记忆丧失和一系列心理社会问题。由于这个问题，美国癫痫协会呼吁对创伤后癫痫进行长期研究。因此，我们对我们的建议进行了调整，以提供满足这一需求的信息。在我们的初步研究中，我们在成年雄性大鼠中使用了一种称为受控皮质撞击（CCI）的TBI模型，发现CCI后癫痫发作阈值不仅降低，而且此后至少6个月继续下降。在这个时候，我们建议长期评估癫痫发作阈值后，横向CCI在整个寿命的成年大鼠，这是约24个月。在此期间，我们计划进行电生理，组织学和生物化学实验在体外和体内技术来评估癫痫发作阈值的海马亚区，包括齿状回，CA 3和CA 1 CCI后每6个月。我们还发现，在我们的初步研究，证据表明，治疗与Bcl-220-34肽可以防止降低癫痫发作后CCI阈值。因此，我们也将在我们的建议中评估这种治疗策略。此外，我们将研究Bcl-220-34肽的潜在作用机制，这可能表明线粒体参与TBI后癫痫发作阈值降低的产生。为此，我们还将评估CCI后有和没有Bcl-220-34肽治疗的线粒体结构和功能。