Optimization of the FPI model for epilepsy therapy development

描述(申请人提供)：在过去的30年里，许多抗癫痫药物(AEDs)被引入，但癫痫发作控制不充分的患者比例保持在~30%不变。这导致了人们对临床前AED筛查中使用的急性癫痫模型的怀疑，因为它们可能无法捕捉到对人类耐药慢性自发性癫痫(CSRSS)的沉淀和控制最重要的机制。因此，迫切需要开发药物耐药癫痫的临床前模型。此外，目前还没有发现预防高危患者癫痫发作的药物，而且还需要癫痫发生的模型。因此，最近的大量工作集中在开发获得性CSRS模型，该模型紧密复制已知的人类致痫的脑侮辱，因此很可能招募与相应的人类综合征相关的生发和癫痫发生机制：中风、头部损伤、早期发热性癫痫发作和缺氧-缺血。我们已经在大鼠中建立了这些病因学上现实的获得性CSRS模型之一，即流体冲击伤(FPI)模型。 创伤后癫痫(PTE)，最近已将其用于鉴定抗癫痫(AE)和抗癫痫(AEG)活性。颅脑损伤在力学上与人类闭合性脑挫裂伤相同，并复制了许多其病理生理后遗症。它表现为新皮质和边缘起源的局灶性自发性癫痫发作，病理与人类PTE相同，以及起始损伤和PTE发病之间的潜伏期。大鼠额叶新皮质比其他脑区对FPI更敏感，导致癫痫的发生比顶叶/枕叶皮质和边缘结构更快，产生的CRSS可被氟烷完全阻断，被丙戊酸盐部分阻断，并对卡马西平和卡马西平具有很强的抗药性。因此，FPI诱导的额叶PTE是一种很有前途的药物筛选耐药癫痫模型。然而，在慢性癫痫模型中，所有基于ECoG的药物筛选都涉及到相当大的成本，包括FPI。需要进一步优化模型，以使FPI具有系统的临床前药物研究的成本效益。为此，我们将对FPI和随之而来的损伤的几个参数进行全面优化。我们将确定是否1)控制急性创伤后呼吸暂停/缺氧可以使PTE的发生率更高和发作频率更均匀，2)损伤的位置和严重程度的变化更能促进额叶癫痫的发生，以及3)硬膜下出血的严重程度预测哪些动物不会成为癫痫患者。这些数据将被用来减少受试者之间的变异性，提高癫痫发生的速度和PTE的发生率，这将允许以成本效益的方式使用FPI模型来识别新的抗癫痫和抗癫痫治疗。 公共卫生相关性：在过去的30年里，许多抗癫痫药物被引入，但癫痫发作控制不充分的患者比例一直保持在30%左右，而且还没有找到治疗癫痫的方法。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种有前景的创伤后癫痫新模型，该模型对经典和新的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.