Optimization of the FPI model for epilepsy therapy development

描述（由申请人提供）：在过去的30年中，已经引入了许多抗癫痫药物（AED），但癫痫发作控制不佳的患者比例保持不变，约为30%。这导致了对临床前AED筛选中采用的急性癫痫发作模型的怀疑，因为它们可能无法捕获对人类耐药性慢性自发复发性癫痫发作（CSRS）的沉淀和控制最重要的机制。因此，迫切需要开发耐药性癫痫的临床前模型。此外，还没有确定预防高危患者癫痫的药物，也需要癫痫发生模型。因此，大量的最近的努力集中在获得性CSRS模型的发展，密切再现脑损伤已知是癫痫在人类中，因此，可能招募的发病机制和癫痫发生相关的相应的人类综合征：中风，头部损伤，早期生活热性惊厥，和缺氧缺血。我们已经在大鼠中开发了这些病因学上现实的获得性CSRS模型之一，即液压冲击损伤（FPI）模型。 创伤后癫痫（PTE），并在最近将其调整为抗癫痫（AE）和抗癫痫（AEG）活性的鉴定。FPI在机械上与人类闭合性脑挫伤相同，并再现其许多病理生理学后遗症。它显示了新皮质和边缘起源的局灶性自发性癫痫发作，病理学与人类PTE相似，以及起始损伤和PTE发作之间的潜伏期。大鼠额叶新皮层对FPI比其他脑区更敏感，导致癫痫发生比顶叶/枕叶皮层和边缘结构更快，并产生CRSS，这些CRSS被氟烷完全阻断，被丙戊酸盐部分阻断，对卡马西平和卡巴氨酯非常耐药。因此，FPI诱导的额叶PTE是一种很有前途的耐药性癫痫模型，用于药物筛选。然而，在慢性癫痫模型中，包括FPI在内的所有基于ECoG的药物筛选都涉及大量成本。需要进一步优化模型，使FPI成本效益的系统性临床前药物研究。为此，我们将进行全面优化的几个参数的FPI和随之而来的伤害。我们将确定1）控制急性创伤后呼吸暂停/缺氧是否会增加PTE的发生率和更均匀的癫痫发作频率，2）损伤位置和严重程度的变化是否会更好地招募额叶癫痫发生，3）硬膜下出血的严重程度是否会预测哪些动物不会癫痫发作。这些数据将用于降低受试者间变异性，并增加癫痫发生的速度和PTE的发生率，这将允许在识别新型抗癫痫和抗癫痫治疗中使用FPI模型的成本效益。 公共卫生相关性：在过去的30年里，许多抗癫痫药物被引入，但癫痫发作控制不佳的患者比例仍然保持在约30%，并且没有发现癫痫的治愈方法。迫切需要更好的癫痫模型来筛选新的抗癫痫和抗癫痫治疗方法。我们提出的研究将优化一个有前途的创伤后癫痫新模型，该模型对经典和新型抗癫痫药物具有耐药性，并使其适用于有效的常规药物筛选。

DESCRIPTION (provided by applicant): Many anti-epileptic drugs (AEDs) have been introduced over the last 30 years, but the proportion of patients with inadequate control of seizures has remained unchanged at ~30%. This has led to doubts about the acute seizure models employed in preclinical AED screening because they may not capture the mechanisms most important for precipitation and control of pharmacoresistant chronic spontaneous recurrent seizures (CSRSs) in humans. Thus, there is an urgent need to develop preclinical models of pharmacoresistant epilepsy. In addition, no agent has been identified that prevents epilepsy in patients at risk, and models of epileptogenesis are also needed. Thus, substantial recent efforts have focused on the development of acquired CSRS models that closely reproduce brain insults known to be epileptogenic in humans and are, thus, likely to recruit mechanisms of ictogenesis and epileptogenesis that are relevant to the corresponding human syndrome: stroke, head injury, early-life febrile seizures, and hypoxia-ischemia. We have developed one of these etiologically realistic acquired CSRS-models in the rat, the fluid percussion injury (FPI) model of posttraumatic epilepsy (PTE), and have recently adapted it to the identification of antiepileptic (AE) and antiepileptogenic (AEG) activity. FPI is mechanically identical to human contusive closed head injury, and reproduces many of its pathophysiological sequelae. It displays focal spontaneous seizures of neocortical and limbic origin, pathology as in human PTE, and a latent period between the initiating injury and the onset of PTE. The rat frontal neocortex is more sensitive to FPI than other brain areas, resulting in faster epileptogenesis than parietal/occipita cortices and limbic structures, and generates CRSSs that are fully blocked by halothane, partially blocked by valproate, and very resistant to carbamazepine and carisbamate. Thus, FPI-induced frontal lobe PTE is a promising model of pharmacoresistant epilepsy for drug screening. However, there are substantial costs involved in all ECoG-based drug screening in chronic epilepsy models, including FPI. Further optimization of the model is needed to make FPI cost-effective for systematic preclinical drug studies. To this end we will conduct a comprehensive optimization of several parameters of FPI and ensuing injury. We will determine whether 1) controlling acute posttraumatic apnea/hypoxia allows higher incidence of PTE and more uniform seizure frequency, 2) variations in location and severity of injury better recruit frontal lobe epileptogenesis, and 3) the severity of subdural hemorrhage predicts which animals will not become epileptic. These data will be used to decrease inter- subject variability, and increase speed of epileptogenesis and incidence of PTE, which will permit cost- effective use of the FPI model in the identification of novel antiepileptic and antiepileptogenic treatments. PUBLIC HEALTH RELEVANCE: Many anti-epileptic drugs have been introduced over the last 30 years, but the proportion of patients with inadequate control of seizures has remained unchanged at ~30%, and no cure for epilepsy has been found. Better models of epilepsy are urgently needed to screen for novel antiepileptic and antiepileptogenic treatments. Our proposed studies will optimize a promising new model of posttraumatic epilepsy that is resistant to classic and new antiepileptic drugs, and adapt it for efficient routine drug screening.