Novel Treatment Strategies for Targeting Posttraumatic Epilepsy

针对创伤后癫痫的新治疗策略

• 批准号: 8597337
• 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/8597337
• 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) 是平民和军人中创伤性脑损伤 (TBI) 的常见后果。尽管已经进行了一些研究来评估这种临床综合征的病理生理学，但尚未在人类 PTE 人群中验证经过验证的治疗方法。我们最近的研究结果表明，大鼠中度液体冲击脑损伤会导致创伤后数周至数月的癫痫阈值降低。神经元和回路兴奋的这种改变得到了行为、电生理学和组织病理学数据的支持。此外，本拨款提案中总结的初步结果表明，TBI 后 30 分钟诱发的适度创伤后低温 (33oC) 会增加癫痫阈值，减少神经元脆弱性和海马体中异常轴突萌芽。因此，本提案将以这些令人兴奋的发现为基础，研究 TBI 后癫痫易感性发展的受体依赖性作用机制，并将首次利用包括适度低温和神经递质受体定向治疗在内的联合治疗方法来改善创伤结果并降低 PTE 的发生率。在具体目标 1 中，将使用包括电生理学和认知评估在内的临床相关结果测量来确定损伤严重程度对亚急性（1 周和 4 周）和慢性（12 周和 1 年）癫痫易感性的影响。损伤严重程度与 PTE 的临床表现相关，但目前还没有直接解决这个问题的实验。在这一系列研究中，将在几个创伤后时间点给予阈下剂量的癫痫发作诱导剂戊四唑（PTZ），以确定是否发生与损伤严重程度相关的癫痫阈值变化。在具体目标 2 中，将评估创伤后由于抑制性 (GABAA) 和兴奋性 (NR2B) 受体功能失衡而导致局部海马回路活动改变的证据。这些研究将确定癫痫持续状态后受体定位的变化是否会影响 TBI 后癫痫易感性的发展。此外，将进行海马区域神经元脆弱性模式以及苔藓纤维发芽的证据，以确定这些创伤性后果是否与癫痫阈值的变化相关。将采用定量免疫细胞化学、蛋白质印迹和原位杂交方法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，在具体目标 3 中，将测试一种新颖的联合治疗策略，包括创伤后适度低温与 NR2B 受体阻滞剂 (Ro 25,6981) 相结合。中枢神经系统损伤后适度低温的益处已得到充分证明，但对于 PTE 的益处尚不清楚。因此，这种组合方法可能是提供治疗 PTE 临床前疗效数据的关键。单一治疗模式的优点和局限性也将直接与这种组合方法进行比较，以评估治疗窗、剂量反应以及治疗效果。根据初步发现，这种组合方法应该能够防止神经元脱落、受体脆弱性以及包括癫痫活动和认知功能在内的行为结果测量。拟议的研究将由一组经验丰富的研究人员进行，他们在 TBI 的病理生理学和治疗方面拥有良好的记录。这些研究的数据有可能用于支持针对这一弱势患者群体的 PTE 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，也是癫痫的后续危险因素。 TBI 不仅影响平民，而且现在被称为最近伊拉克和阿富汗战争的“标志性伤害”。除了与所有类型的 TBI 相关的认知问题外，根据对这些退伍军人的评估进行分析，创伤后癫痫发作率无疑在返回的士兵中也很普遍。然而，目前尚无有效的治疗策略来预防创伤后癫痫（PTE）。目前的提案将建立在最近的研究基础上，研究损伤严重程度相关的癫痫易感性变化和相关的认知功能障碍，以及适合治疗的病理机制。预计该提案的结果将对我们对待军队和平民 PTE 的方式产生影响。