Optimization of the FPI model for epilepsy therapy development

描述（由申请人提供）：在过去的30年里，许多抗癫痫药物（aed）被引入，但癫痫发作控制不足的患者比例保持不变，约为30%。这导致了对临床前AED筛查中使用的急性发作模型的怀疑，因为它们可能没有捕捉到人类耐药慢性自发性复发性癫痫发作（CSRSs）沉淀和控制最重要的机制。因此，迫切需要建立抗药癫痫的临床前模型。此外，还没有发现预防高危患者癫痫的药物，也需要癫痫发生的模型。因此，最近大量的工作集中在发展获得性CSRS模型上，这些模型密切再现了已知的人类致癫痫的脑损伤，因此，可能会招募与相应的人类综合征相关的icogenesis和epilepsy发生机制：中风、头部损伤、生命早期发热性癫痫发作和缺氧缺血。我们在大鼠身上建立了一种病因学上符合实际的获得性csrs模型——液体撞击损伤（FPI）模型

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.