Validation of a novel animal model of post-traumatic epilepsy

验证一种新型创伤后癫痫动物模型

• 批准号: 10214538
• 负责人: Cha-Min Tang
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214538
• 关键词: Anatomy; Animal Model; Anticonvulsants; Antiepileptic Agents; Area; Behavioral; Caring; Characteristics; Chronic; Complex; Complication; Deafferentation procedure; Department of Defense; Disease; Down-Regulation; Drug Prescriptions; Drug Screening; Electrodes; Enhancers; Epilepsy; Exclusion; Face; Follow-Up Studies; Frequencies; Functional disorder; Hippocampus (Brain); Injury; Keppra; Lateral; Lead; Lesion; Levetiracetam; Life; Liquid substance; Medical; Mission; Modeling; Mus; Pathologic; Penetrating Brain Injury; Penetration; Percussion; Post-Traumatic Epilepsy; Preparation; Procedures; Rattus; Reporting; Research; Resources; Seizures; Slice; Stimulus; Synapses; Testing; Time; Tissues; Traumatic Brain Injury; Validation; Variant; Veterans; base; combat; combat casualty; controlled cortical impact; disability; drug development; drug discovery; experimental study; improved; improved outcome; in vivo; military veteran; mouse model; new therapeutic target; novel; postsynaptic; presynaptic; screening; segregation

PTE (posttraumatic epilepsy) has been identified by the VA as a priority area for research. Current medical therapy for this condition is inadequate. No anticonvulsant has yet been demonstrated to be specifically effective against PTE. The animal model used for screening anticonvulsants (AEDs) greatly influences which compounds are identified. One consequence is that standard animal models seem to consistently identify compounds with similar actions. Since there is no good PTE animal model, AEDs especially effective for PTE have not been identified. Evidence of the benefits of novel animal models is the identification of levetiracetam (Keppra), currently the most prescribe drug for epilepsy. The more standard animal models had failed to identify its antiepileptic activity. Current PTE animal models such as lateral fluid percussion and controlled cortical impact are not practical for screening AEDs because the timing of seizures cannot be controlled. We have developed a model of penetration injury induced epilepsy. It is a variation on the theme of Dave Prince’s partial cortical isolation PTE model. The current model solves two critical weakness of the cortical undercutting model by utilizing the simpler anatomy of the hippocampus. First, sectioning the Schaffer Collateral that connect the CA3 and CA1 region of the rat hippocampus can create a region that predominantly contains reactive presynaptic changes (i.e. aberrant synaptic reorganization) and a region that contain postsynaptic changes (deafferentation induced dendritic hyperexcitability). This segregation of reactive mechanisms cannot be achieved in the cortex. Consequently, it makes it possible to more easily dissect the underlying complex mechanisms of PTE. Secondly, sectioning of the Schaffer Collateral does NOT block the spread of seizure from the seizure focus, as is the case with the cortical undercutting model. Thus, behavioral seizures can be observed. A third advantage from a drug discovery perspective is that, similar to the kindling model, seizures can be reliably evoked by a weak triggering electrical stimulus. This is operationally important for drug screening. One cannot wait for a seizure to occur when screening drugs. A useful animal model has to produce seizures on demand. In preliminary studies we have gathered compelling evidence that this novel PTE animal model can reliably produce behavioral and electrographic limbic seizures on demand. At this moment a compelling and unusual opportunity exists for a successful rational drug development. A novel therapeutic target for PTE, dendritic SK2 channels, has been identified. A novel animal model of PTE possessing the latter dysfunction has been developed. And a class of SK2 enhancers that can reverse that dysfunction has been discovered. We seek to make the most from the confluence of these discoveries and the opportunity they offer.

PTE（创伤后癫痫）已被VA确定为优先领域， research.目前对这种情况的医学治疗是不够的。目前还没有抗惊厥药 已被证明对PTE特别有效。动物模型用于 抗惊厥药（AED）的筛选极大地影响了哪些化合物被鉴定。一 结果是，标准动物模型似乎一致地鉴定出具有以下特征的化合物： 类似的行动。由于目前还没有良好的PTE动物模型， 尚未被确认。新动物模型的益处的证据是鉴定出 左乙拉西坦（凯普拉），目前最常用于癫痫的处方药。更标准的 动物模型未能确定其抗癫痫活性。目前的PTE动物模型，如 侧向液压冲击和控制皮质撞击对于筛选AED是不切实际的 因为癫痫发作的时间无法控制。 我们建立了一种穿透伤致癫痫模型。这是一个变异的 Dave Prince的部分皮层隔离PTE模型的主题。目前的模型解决了两个关键问题 皮质底切模型的弱点，通过利用更简单的解剖结构， 海马体。首先，切片连接CA3和CA1区域的Schaffer侧支， 大鼠海马可以产生一个主要含有反应性突触前 变化（即异常突触重组）和包含突触后变化的区域 （传入神经阻滞诱导的树突过度兴奋）。这种反应机制的分离 无法在大脑皮层中实现。因此，它使得可以更容易地解剖 PTE的潜在复杂机制。其次，Schaffer抵押品的分割 不阻止癫痫发作从癫痫病灶扩散，如皮质 削弱模型因此，可以观察到行为癫痫发作。药物的第三个优势是 发现的观点是，类似于点燃模型，癫痫发作可以可靠地诱发由一个 微弱的触发电刺激这对于药物筛选在操作上是重要的。一 不能等到癫痫发作时才筛选药物。一个有用的动物模型 按需扣押。在初步研究中，我们收集了令人信服的证据， 新的PTE动物模型可以可靠地产生行为和电描记边缘癫痫发作， 需求 在这个时刻，一个令人信服的和不寻常的机会存在一个成功的合理的药物 发展一种新的治疗靶点PTE，树突状SK2通道，已被确定。一 已经开发了具有后一种功能障碍的PTE的新动物模型。和一类 已经发现了可以逆转这种功能障碍的SK2增强剂。我们力求使 大部分来自于这些发现和它们提供的机会。