Validation of a novel animal model of post-traumatic epilepsy

PTE(创伤后癫痫)已被退伍军人管理局确定为优先治疗的领域 研究。目前对这种情况的药物治疗是不够的。目前还没有抗惊厥的药物 已被证明对PTE特别有效。应用于临床的动物模型 抗惊厥药物(AEDs)的筛选对识别哪些化合物有很大影响。一 结果是，标准的动物模型似乎一致地将化合物与 类似的行动。由于目前尚无良好的PTE动物模型，AEDs对PTE尤其有效 还没有确定身份。新的动物模型益处的证据是确定 左乙拉西坦(Keppra)，目前治疗癫痫最多的处方药。越标准越好 动物模型未能确定其抗癫痫活性。目前的PTE动物模型，如 侧向液体冲击和受控皮质冲击不适用于AEDs的筛查 因为癫痫发作的时间是无法控制的。 我们建立了一种穿透性损伤诱发癫痫的模型。它是一个变种 戴夫·普林斯的部分皮质隔离PTE模型的主题。当前的模型解决了两个关键问题 利用大脑皮质下切面模型的简单解剖学研究 海马体。首先，切开连接CA3和CA1区的Schaffer侧支 大鼠的海马体可以创建一个主要包含反应性突触前的区域 变化(即异常突触重组)和包含突触后变化的区域 (去传入诱发的树突状超兴奋性)。这种反应机制的分离 不能在大脑皮层实现。因此，它使得更容易地剖析 PTE潜在的复杂机制。其次，切分Schaffer抵押品确实 不能像皮质一样，阻止癫痫从癫痫灶扩散。 切入模型。因此，可以观察到行为性癫痫发作。药物带来的第三个好处 发现的观点是，与点燃模型类似，癫痫发作可以通过一种可靠的 弱触发电刺激。这对于药物筛选具有重要的操作意义。一 在筛选药物时，不能等待癫痫发作发生。一个有用的动物模型必须产生 按需查封。在初步研究中，我们收集了令人信服的证据，证明 新的PTE动物模型能可靠地产生行为和脑电边缘癫痫发作 需求。 此时此刻，对于一种成功的理性药物来说，存在着一个令人信服的不同寻常的机会 发展。已经确定了PTE的一个新的治疗靶点，树突状SK2通道。一个 具有后一种功能障碍的PTE动物模型已被开发出来。以及一类 可以逆转这种功能障碍的SK2增强剂已经被发现。我们寻求使 大部分来自这些发现和它们提供的机会的汇合。

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.