Model of Idiopathic Infantile Spasms

描述（由申请人提供）：婴儿痉挛属于儿童灾难性癫痫综合征。这些癫痫难以治疗，并伴有进行性认知功能下降。婴儿痉挛被分类为症状性（与诊断的脑病变相关）或特发性/隐源性（没有病变可以显示）。治疗是激素，促肾上腺皮质激素（ACTH）是首选药物，其次是皮质类固醇和氨己烯酸。所有这些药物都有严重的副作用。没有适合的特发性/隐源性婴儿痉挛症动物模型可用于测试对癫痫发作和相关认知下降具有更好疗效且副作用有限的新推定治疗。由于ACTH和皮质类固醇对婴儿痉挛症有积极作用，我们假设大脑下丘脑-垂体-肾上腺轴控制系统的损害可能参与建立适当的特发性/隐源性婴儿痉挛症模型。我们提出了一种新的婴儿痉挛症的动物模型，在大鼠出生前暴露于beta3。然后通过全身性N-甲基-D-天冬氨酸（NMDA）注射在出生后触发癫痫特异性痉挛发作。痉挛类似于婴儿痉挛。此外，在痉挛期间存在类似于人类电递减反应的EEG抑制，并且痉挛对ACTH治疗敏感。在本提案中，我们将使用行为和电描记癫痫发作、行为/认知结果（单杠、高架十字迷宫、旷场和Morris水迷宫试验）和使用长期EEG/视频监测筛查自发性癫痫发作的发展，基于产前暴露于beta3并在婴儿期用NMDA触发的特发性/隐源性婴儿痉挛的新模型进行表征。此外，我们将通过使用对人类婴儿痉挛有效的药物（ACTH、氨己烯酸、泼尼松）及其对行为和电图癫痫发作、行为/认知结果和发育后期癫痫发作易感性的影响来验证该模型。该提案的目标是开发足够可靠但相对简单的婴儿痉挛模型，可用于新抗惊厥药物和治疗程序的常规测试。根据我们收集的结果，我们将继续在NIH公告（PAR-06-189）的意义上进行新治疗的临床前开发。婴儿痉挛是儿童期的毁灭性癫痫，尽管有治疗，但仍与严重的发育衰退有关。开发新的有效的药物和治疗策略，将改善结果取决于婴儿痉挛症的动物模型的可用性。在这里，我们提出了一个新的模型婴儿痉挛症引发的年轻动物产前脑损伤后。该提案的目的是进一步表征模型，包括行为和认知结果，并通过使用对人类婴儿痉挛症有效的疗法来验证模型。目标是开发足够可靠但相对简单的婴儿痉挛模型，可用于新的更安全，更有效的治疗方法的常规测试。

DESCRIPTION (provided by applicant): Infantile spasms belong to catastrophic epilepsy syndromes of childhood. These epilepsies are intractable to treatment and are associated with progressive cognitive decline. Infantile spasms are classified as symptomatic (associated with a diagnosed brain lesion) or idiopathic/cryptogenic (no lesion can be revealed). Therapy is hormonal, adrenocorticotropic hormone (ACTH) is a drug of choice followed by corticosteroids and vigabatrin. All these drugs have serious side effects. There is no appropriate animal model of idiopathic/cryptogenic infantile spasms suitable for testing new putative treatments with better efficacy on seizures and associated cognitive decline, and with limited side effects. Because ACTH and corticosteroid have positive effects on infantile spasms, we hypothesized that impairment of the brain hypothalamus-pituitary-adrenal axis control systems could be involved in building the appropriate model of the idiopathic/cryptogenic infantile spasms. We propose a new animal model of infantile spasms created in rats prenatally exposed to betamethasone. Age-specific spastic seizures are then triggered postnatally by systemic N-methyl-D-aspartate (NMDA) injection. The spasms are similar to infantile spasms. Additionally, there is EEG suppression during the spasms similar to electrodecremental response in humans, and the spasms are sensitive to ACTH therapy. In this proposal we will characterize this new model of idiopathic/cryptogenic infantile spasms based on prenatal exposure to betamethasone and triggered during infancy with NMDA using behavioral and electrographic seizures, behavioral/cognitive outcome (horizontal bar, elevated plus maze, open field and Morris Water Maze tests) and screening for the development of spontaneous seizures using long-term EEG/videomonitoring. Further, we will validate the model by using drugs effective against infantile spasms in humans (ACTH, vigabatrin, prednisone) and their effects on behavioral and electrographic seizures, behavioral/cognitive outcome and seizure susceptibility later in the development. The goal of this proposal is to develop sufficiently reliable yet relatively simple model of infantile spasms, which could be used for routine testing of new anticonvulsant drugs and treatment procedures. Based on the results we collect, we will continue in preclinical development of new treatments in the sense of the NIH announcement (PAR-06-189).Infantile spasms are devastating epilepsy of childhood, which is associated with severe developmental decline despite the treatments. Development of new effective drugs and treatment strategies that would improve the outcome depends on availability of an animal model of infantile spasms. Here we propose a new model for infantile spasms triggered in young animals after prenatal brain impairment. Purpose of this proposal is to further characterize the model including behavioral and cognitive outcome and verify the model by using therapies effective in human infantile spasms. The goal is to develop sufficiently reliable yet relatively simple model of infantile spasms, which could be used for routine testing of new safer and more effective treatments.