Novel Treatment Strategies for Targeting Posttraumatic Epilepsy

针对创伤后癫痫的新治疗策略

• 批准号: 8242623
• 负责人: Helen M Bramlett
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 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/8242623
• 关键词: Address; Afghanistan; Applications Grants; Attenuated; Behavioral; Brain Injuries; Chronic; Clinic; Clinical; Clinical Trials; Cognitive; Combined Modality Therapy; Convulsants; Craniocerebral Trauma; Data; Development; Disease; Dose; Down-Regulation; Drops; Electrophysiology (science); Epilepsy; FDA approved; Functional disorder; GABA Receptor; Glutamates; Grant; Hippocampus (Brain); Hour; Human; Impact Seizures; Impaired cognition; In Situ Hybridization; In Vitro; Incidence; Injury; Investigation; Iraq; Laboratories; Lead; Liquid substance; Messenger RNA; Military Personnel; Modeling; Modification; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; NR2B NMDA receptor; Neurons; Neurotransmitter Receptor; Outcome; Outcome Measure; Pattern; Pentylenetetrazole; Percussion; Pharmaceutical Preparations; Pharmacotherapy; Population; Predisposition; Prevention; Proteins; Rattus; Research; Research Personnel; Risk Factors; Seizures; Series; Severities; Soldier; Status Epilepticus; Syndrome; Testing; Therapeutic; Time; Toxic effect; Trauma; Traumatic Brain Injury; Treatment Efficacy; United States; Veterans; War; Western Blotting; axonal sprouting; base; central nervous system injury; clinical efficacy; clinically relevant; cognitive function; effective therapy; efficacy testing; experience; improved; mortality; mossy fiber; natural hypothermia; neuron loss; neuronal excitability; neuronal patterning; novel; patient population; pre-clinical; preclinical study; prevent; public health relevance; receptor; receptor function; receptor upregulation; research study; response; treatment strategy

DESCRIPTION (provided by applicant): Posttraumatic epilepsy (PTE) is a frequent consequence of traumatic brain injury (TBI) in both the civilian and military population. Although some investigations have been conducted to evaluate the pathophysiology of this clinical syndrome, no proven therapies have been validated in the human PTE population. Our recent findings demonstrate that moderate fluid percussion brain injury in rats leads to reduced seizure threshold weeks to months after trauma. This alteration in neuronal and circuit excitation is supported by behavioral, electrophysiological and histopathological data. In addition, preliminary findings summarized in this grant proposal demonstrate that modest posttraumatic hypothermia (33oC) induced 30 minutes after TBI increases seizure threshold, reduces neuronal vulnerability and aberrant axonal sprouting in the hippocampus. Therefore, the present proposal will build on these exciting findings by investigating receptor-dependent mechanisms of action on the development of seizure susceptibility after TBI and will for the first time utilize a combination therapeutic approach including modest hypothermia and neurotransmitter receptor directed therapy to improve traumatic outcome and reduce the incidence of PTE. In Specific Aim 1, the impact of injury severity on subacute (1 and 4 weeks) and chronic (12 wks and 1 yr) seizure susceptibility using clinically relevant outcome measures including electrophysiology and cognitive assessment will be determined. Injury severity has been associated with the clinical manifestation of PTE but there currently are no experiments directly addressing this issue. In this series of studies, a subthreshold dose of the seizure-inducing agent pentylenetetrazole (PTZ) will be given at several post-traumatic time points to determine if injury severity- dependent changes in seizure threshold occur. In Specific Aim 2, evidence for alterations in local hippocampal circuit activity after trauma due to an imbalance in inhibitory (GABAA) and excitatory (NR2B) receptor function will be assessed. These studies will determine if changes in receptor localization seen after status epilepticus influence the development of seizure susceptibility after TBI. In addition, patterns of neuronal vulnerability in hippocampal regions as well as evidence for mossy fiber sprouting will be conducted to determine if these traumatic consequences can be correlated with changes in seizure threshold. Quantitative immunocytochemical, western blotting and in situ hybridization approaches for regional and cellular protein and mRNA assessment will be performed to determine these injury severity-dependent changes. Finally, in Specific Aim 3, a novel combination treatment strategy including modest posttraumatic hypothermia combined with a NR2B receptor blocker (Ro 25,6981) will be tested. The benefits of modest hypothermia are well documented after CNS injury but are unknown for PTE. Therefore, this combination approach may be the key to providing pre-clinical efficacy data in treating PTE. The benefits and limitations of single treatment paradigms will also be directly compared to this combination approach to assess therapeutic window, dose response as well as therapeutic efficacy. Based on preliminary findings, this combination approach should provide protection against neuronal drop-out, receptor vulnerability as well as behavioral outcome measures including seizure activity and cognitive function. The proposed studies will be performed by a group of experienced investigators that have a proven track record in the pathophysiology and treatment of TBI. Data from these studies could potentially be used to support clinical trials targeting PTE in this vulnerable patient population. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States and is a subsequent risk factor for epilepsy. TBI not only effects civilian populations but is now known as the "signature injury" of the recent wars in Iraq and Afghanistan. In addition to cognitive problems associated with all types of TBI, posttraumatic seizure incidence rates will undoubtedly be prevalent in returning soldiers as assessment of these veterans is analyzed. However, there are currently no effective treatment strategies for the prevention of posttraumatic epilepsy (PTE). The present proposal will build on recent investigations to study injury severity- dependent changes on seizure susceptibility and associated cognitive dysfunction along with targeting pathomechanisms that would be amenable to treatment. It is anticipated that findings from this proposal will have an impact on the way we treat PTE in both military as well as civilian populations.

描述（由申请人提供）： 创伤后癫痫（PTE）是平民和军事人口中创伤性脑损伤（TBI）的经常结果。尽管已经进行了一些研究以评估该临床综合征的病理生理学，但在人类PTE种群中尚未验证尚未验证的疗法。我们最近的发现表明，大鼠中等液体打击乐导致创伤后数周到几个月的癫痫发作阈值降低。神经元和电路激发的这种改变得到了行为，电生理和组织病理学数据的支持。此外，该赠款提案中总结的初步发现表明，在TBI增加癫痫发作阈值30分钟后，适度的创伤后体温过低（33OC）诱导了神经元脆弱性和海马中的异常轴突芽。因此，本提案将通过研究对受体依赖性的作用机制来建立在TBI后发作易感性发展的作用机制，并首次使用组合治疗方法，包括适度的体温过低和神经释放剂受体受体定向治疗，以改善PTE的发病率和减少PTE的发病率。在特定的目标1中，使用临床相关的结果指标，包括电生理学和认知评估，损伤严重程度对亚急性（1和4周）以及慢性（12周和1年）的癫痫敏感性的影响。损伤严重程度与PTE的临床表现有关，但目前没有直接解决此问题的实验。在这一系列的研究中，将在几个创伤后时间点给出癫痫发作剂螺旋甲酸（PTZ）的亚阈值剂量，以确定是否发生癫痫发作阈值的损伤严重程度依赖性变化。在特定的目标2中，将评估创伤后局部海马电路活性改变的证据，这将评估抑制性（GABAA）和兴奋性（NR2B）受体功能的不平衡。这些研究将确定在癫痫持续状态下观察到的受体定位的变化是否会影响TBI后癫痫敏感性的发展。此外，将进行海马区域神经元脆弱性的模式以及苔藓纤维发芽的证据，以确定这些创伤后果是否与癫痫发作阈值的变化相关。定量免疫细胞化学，蛋白质印迹和原位杂交方法将进行区域和细胞蛋白和mRNA评估，以确定这些损伤严重程度依赖性变化。最后，在特定的目标3中，将测试一种新型的组合治疗策略，包括适度的创伤后体温过低，并结合NR2B受体阻滞剂（RO 25,6981）。中枢神经系统损伤后，适度的体温过低的好处有充分的记录，但PTE未知。因此，这种组合方法可能是在治疗PTE中提供临床前功效数据的关键。单个治疗范例的益处和局限性也将直接与这种评估治疗窗口，剂量反应以及治疗功效的组合方法进行比较。基于初步发现，这种组合方法应提供保护神经元辍学，受体脆弱性以及行为结果指标，包括癫痫发作和认知功能。拟议的研究将由一组经验丰富的研究人员进行，这些研究人员在TBI的病理生理学和治疗方面具有良好的记录。这些研究的数据可能有可能用于支持针对该脆弱患者人群中PTE的临床试验。 公共卫生相关性： 创伤性脑损伤（TBI）是美国发病率和死亡率的主要原因，是癫痫病的随后危险因素。 TBI不仅影响平民，而且现在被称为伊拉克和阿富汗最近战争的“签名伤害”。除了与所有类型的TBI相关的认知问题外，由于分析了对这些退伍军人的评估，创伤后癫痫发病率无疑将很普遍。但是，目前尚无有效的治疗策略来预防创伤后癫痫（PTE）。本提案将基于最近的调查，以研究疾病严重程度的癫痫敏感性和相关认知功能障碍，以及针对治疗的病原机制。可以预料，该提案的发现将影响我们对待军事和平民人口的PTE的方式。