Galanopoulou Aristea S, Moshé Solomon L
Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Laboratory of Developmental Epilepsy, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Laboratory of Developmental Epilepsy, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Neurobiol Dis. 2015 Jul;79:135-49. doi: 10.1016/j.nbd.2015.04.015. Epub 2015 May 9.
Early onset and infantile epileptic encephalopathies (EIEEs) are usually associated with medically intractable or difficult to treat epileptic seizures and prominent cognitive, neurodevelopmental and behavioral consequences. EIEEs have numerous etiologies that contribute to the inter- and intra-syndromic phenotypic variability. Etiologies include structural and metabolic or genetic etiologies although a significant percentage is of unknown cause. The need to better understand their pathogenic mechanisms and identify better therapies has driven the development of animal models of EIEEs. Several rodent models of infantile spasms have emerged that recapitulate various aspects of the disease. The acute models manifest epileptic spasms after induction and include the NMDA rat model, the NMDA model with prior prenatal betamethasone or perinatal stress exposure, and the γ-butyrolactone induced spasms in a mouse model of Down syndrome. The chronic models include the tetrodotoxin rat model, the aristaless related homeobox X-linked (Arx) mouse models and the multiple-hit rat model of infantile spasms. We will discuss the main features and findings from these models on target mechanisms and emerging therapies. Genetic models have also provided interesting data on the pathogenesis of Dravet syndrome and proposed new therapies for testing. The genetic associations of many of the EIEEs have also been tested in rodent models as to their pathogenicity. Finally, several models have tested the impact of subclinical epileptiform discharges on brain function. The impact of these advances in animal modeling for therapy development will be discussed.
早发性和婴儿期癫痫性脑病（EIEEs）通常与药物难治性或难以治疗的癫痫发作以及显著的认知、神经发育和行为后果相关。EIEEs有众多病因，这些病因导致了综合征间和综合征内的表型变异性。病因包括结构性、代谢性或遗传性病因，尽管很大一部分病因不明。为了更好地理解其致病机制并确定更好的治疗方法，推动了EIEEs动物模型的发展。已经出现了几种婴儿痉挛症的啮齿动物模型，这些模型概括了该疾病的各个方面。急性模型在诱导后表现出癫痫痉挛，包括NMDA大鼠模型、产前使用倍他米松或围产期应激暴露后的NMDA模型，以及唐氏综合征小鼠模型中γ-丁内酯诱导的痉挛。慢性模型包括河豚毒素大鼠模型、无尾相关同源盒X连锁（Arx）小鼠模型和婴儿痉挛症的多重打击大鼠模型。我们将讨论这些模型在靶点机制和新兴治疗方法方面的主要特征和发现。遗传模型也提供了关于德雷维特综合征发病机制的有趣数据，并提出了新的治疗方法进行测试。许多EIEEs的遗传关联也在啮齿动物模型中测试了其致病性。最后，一些模型测试了亚临床癫痫样放电对脑功能的影响。将讨论这些动物模型进展对治疗开发的影响。
