TBI epileptogenesis: pathologic hippocampal L-glut synaptic plasticity

TBI 癫痫发生：病理性海马 L-谷胱甘肽突触可塑性

• 批准号: 8916636
• 负责人: John T. Slevin
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916636
• 关键词: Acute; Affect; Afghanistan; Amino Acid Transporter; Amygdaloid structure; Animal Model; Animals; Antiepileptic Agents; Antiepileptogenic; Behavior; Chronic; Clinical Research; Dependovirus; Development; Electrodes; Enzymes; Epilepsy; Epileptogenesis; Evaluation; Event; Evolution; Excitatory Amino Acids; Exocytosis; Extracellular Space; FDA approved; Glutamate Transporter; Glutamates; Goals; Healthcare Systems; Hippocampal Formation; Hippocampus (Brain); Human; Individual; Injury; Investigation; Iraq; Kindling (Neurology); Label; Lateral; Lead; Left; Levetiracetam; Life; Measures; Microelectrodes; Military Personnel; Modeling; Molecular; Molecular Target; Monitor; Morbidity - disease rate; Neuraxis; Neurons; Neurotransmitters; Pathologic; Patients; Population; Post-Traumatic Epilepsy; Probability; Process; Recovery; Regulation; Research; Residual state; Risk Factors; SNAP receptor; Signal Transduction; Site; Soldier; Staging; Survivors; Synapses; Synaptic plasticity; System; Techniques; Telemetry; Testing; Therapeutic; Therapeutic Intervention; Tissues; Traumatic Brain Injury; United States; United States Department of Veterans Affairs; Veterans; Western Blotting; base; combat; dentate gyrus; economic cost; fluid percussion injury; insight; irritation; mortality; neurotransmission; neurotransmitter release; neurotransmitter reuptake; novel; novel strategies; presynaptic; relating to nervous system; reuptake; therapeutic target; uptake

DESCRIPTION (provided by applicant): Project Summary The molecular mechanism that underlies evolution to post-traumatic epilepsy (PTE) in individuals with traumatic brain injury (TBI) is unknown. It has been suggested that the development of PTE following TBI is the combined result of kindling epileptogenesis during the early stages of recovery and triggering by residual irritation from damaged neural tissue. Glutamate, the major excitatory neurotransmitter (NT) in the central nervous system, must be tightly regulated to allow for proper neuronal signaling without creating excessive excitation. TBI produces an increase in glutamate release into the extracellular space and a concurrent decrease in the ability of excitatory amino acid transporters to reuptake glutamate that may lead to its accumulation, propagating secondary damage cascades and producing aberrant neuronal signaling. We suggest that the enhanced hippocampal glutamate levels seen post-TBI are in part due to changes of the neurosecretory machinery and SNARE regulators and/or re-sequestration process. Left unchecked, these changes become drivers of post-TBI epileptogenesis leading to PTE. The hypothesis that pathologic adaptation of inherent hippocampal glutamatergic synaptic plasticity promotes post-TBI epileptogenesis will be tested through three specific aims in animals (and appropriate controls) that have been administered a lateral fluid percussion injury (LFPI) and then monitored by telemetry until electroencephalographic (EEG) evidence of epileptiform activity: (1) Measure of tonic glutamate levels and evoked glutamateamate release in the hippocampal formation of epileptic and non-epileptic animals after moderate LFPI through use of a novel microarray electrode system. In tissue from hippocampal formation of these same animals we will use Western blotting techniques to quantify (2) components of the neurotransmitter release process and (3) certain glutamate transporters. Investigation of this putative relationship between aberrant glutamate neuronal exocytosis/resequestration and PTE will provide insight into potential mechanisms by which glutamate neurotransmission is regulated and into the molecular events of epileptogenesis as well as provide potential foci for therapeutic intervention. The long-term goal of this project is to restore to normal aberrant mechanisms associated with TBI-associated epileptogenesis. There are indications from animal studies that several newer FDA-approved and actively used antiepileptic drugs, e.g. levetiracetam and lacosamide, may also act as antiepileptogenic agents through effect on glutamate neurotransmission. Such agents would be appropriate compounds for further mechanistic evaluation in animals and clinical studies in PTE patients if the studies proposed here suggest that chronic dysregulation of glutamatergic release is associated with epileptogenesis. Pretransfection with a recently developed adeno-associated virus for the GLT-1 transporter to enhance glutamate reuptake, currently under investigation by one of us, may provide yet another, novel approach to target a specific mechanism involved in glutamate regulation should these studies confirm a glutamate transporter abnormality is associated with development of PTE.

描述（由申请人提供）： 创伤性脑损伤（TBI）患者演变为创伤后癫痫（PTE）的分子机制尚不清楚。有人认为，创伤性脑损伤后PTE的发展是在恢复的早期阶段点燃癫痫发生和受损神经组织的残余刺激触发的综合结果。谷氨酸是中枢神经系统中的主要兴奋性神经递质（NT），必须严格调节以允许适当的神经元信号传导而不产生过度兴奋。TBI导致谷氨酸释放到细胞外空间的增加，同时兴奋性氨基酸转运蛋白再摄取谷氨酸的能力降低，这可能导致其积累，传播继发性损伤级联反应并产生异常神经元信号传导。我们认为TBI后海马谷氨酸水平的增强部分是由于神经分泌机制和SNARE调节剂和/或再隔离过程的变化。如果不加以控制，这些变化将成为TBI后癫痫发生的驱动因素，导致PTE。我们将通过三个具体的动物实验来验证海马神经元突触可塑性的病理适应性促进脑外伤后癫痫发生的假设（和适当的对照组），已经给予侧向液压冲击损伤（LFPI），然后通过遥测监测，直到脑电图（EEG）证据癫痫样活动：（1）通过使用新的微阵列电极系统测量中度LFPI后癫痫和非癫痫动物的海马结构中的紧张性谷氨酸水平和诱发的谷氨酸释放。在这些相同动物的海马结构组织中，我们将使用蛋白质印迹技术定量（2）神经递质释放过程的组分和（3）某些谷氨酸转运蛋白。对异常谷氨酸神经元胞吐/再定位和PTE之间的这种假定关系的研究将提供对谷氨酸神经传递调节的潜在机制和癫痫发生的分子事件的深入了解，并为治疗干预提供潜在的焦点。该项目的长期目标是恢复与TBI相关癫痫发生相关的正常异常机制。动物研究表明，几种较新的FDA批准和积极使用的抗癫痫药物，如左乙拉西坦和拉考沙胺，也可能通过影响谷氨酸神经传递作为抗癫痫药物。如果本文提出的研究表明，多巴胺能释放的慢性失调与癫痫发生相关，则此类药物将是用于动物中进一步机制评价和PTE患者临床研究的合适化合物。预转染与最近开发的腺相关病毒的GLT-1转运蛋白，以提高谷氨酸再摄取，目前正在调查中的一个我们，可能会提供另一种新的方法来靶向参与谷氨酸调节的特定机制，这些研究应确认谷氨酸转运蛋白异常与PTE的发展。