Model of Idiopathic Infantile Spasms

描述(申请人提供)：婴儿痉挛属于儿童灾难性癫痫综合征。这些癫痫很难治疗，并与进行性认知能力下降有关。婴儿痉挛被归类为症状性(与确诊的脑部病变有关)或特发性/隐源性(未发现病变)。治疗需要激素，促肾上腺皮质激素(ACTH)是首选药物，其次是皮质类固醇和Vigabatrin。所有这些药物都有严重的副作用。目前还没有合适的特发性/隐源性婴儿痉挛的动物模型适合于测试新的假定治疗方法，这些治疗方法对癫痫发作和相关的认知能力下降具有更好的疗效，并且副作用有限。由于ACTH和皮质类固醇对婴儿痉挛有积极作用，我们推测脑下丘脑-垂体-肾上腺轴控制系统的损伤可能参与了特发性/隐源性婴儿痉挛模型的建立。我们提出了一种新的婴儿痉挛动物模型，该模型建立在产前暴露于倍他米松的大鼠身上。然后由全身注射N-甲基-D-天冬氨酸(NMDA)在出生后触发特定年龄的痉挛发作。痉挛类似于婴儿痉挛。此外，在痉挛期间有脑电抑制，类似于人类的电递减反应，并且痉挛对ACTH治疗敏感。在这项提案中，我们将通过行为和电信号发作、行为/认知结果(单杠、高架迷宫、开阔场地和Morris水迷宫测试)和长期脑电/视频监测筛选自发发作的发展，来表征这一新的特发性/隐源性婴儿痉挛模型，该模型基于产前暴露于倍他米松，并在婴儿时期触发NMDA发作。此外，我们将通过使用对人类婴儿痉挛有效的药物(ACTH、Vigabatrin、强的松)以及它们对发育后期的行为和电信号癫痫发作、行为/认知结果和癫痫发作易感性的影响来验证该模型。这项建议的目标是开发足够可靠但相对简单的婴儿痉挛模型，用于新的抗惊厥药物和治疗程序的常规测试。基于我们收集的结果，我们将继续NIH公告(PAR-06-189)意义上的临床前新疗法的开发。婴儿痉挛是儿童时期毁灭性的癫痫，尽管进行了治疗，但与严重的发育衰退有关。开发新的有效药物和治疗策略以改善结果取决于婴儿痉挛动物模型的可用性。在这里，我们提出了一种新的婴儿痉挛模型，该模型在幼年动物出生前脑损伤后引发。这项建议的目的是进一步描述该模型的特征，包括行为和认知结果，并通过使用对人类婴儿痉挛有效的疗法来验证该模型。其目标是开发足够可靠但相对简单的婴儿痉挛模型，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.