Model of Idiopathic Infantile Spasms

特发性婴儿痉挛模型

• 批准号: 7456827
• 负责人: LIBOR VELISEK
• 金额: $ 21.79万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7456827
• 关键词: Abbreviations; Adrenal Cortex Hormones; Adrenal Glands; Adverse effects; Age; Age-Months; Animal Model; Anticonvulsants; Behavioral; Betamethasone; Brain; Child; Childhood; Cognitive; Corticotropin; Corticotropin-Releasing Hormone; Cryptogenic West Syndrome; Cytokine Inducible SH2-Containing Protein; Development; Diagnosis; Drug usage; Electroencephalogram; Electroencephalography; Epilepsy; Etiology; Exposure to; Goals; Hormonal; Human; Hypothalamic structure; Hypsarrhythmia; Impaired cognition; Impairment; Infantile spasms; Injection of therapeutic agent; Intractable Epilepsy; Lesion; Mental Retardation; Mentally Disabled Persons; Modeling; N-Methylaspartate; Neuraxis; Outcome; Patients; Pattern; Pharmaceutical Preparations; Pituitary Gland; Pituitary-Adrenal System; Predisposition; Prednisone; Procedures; Purpose; RBM5 gene; Rattus; Screening procedure; Seizures; Signal Transduction; Spasm; Spastic; Syndrome; System; Testing; Therapeutic; United States National Institutes of Health; Validation; Vigabatrin; Water; age related; base; day; hormone therapy; improved; infancy; juvenile animal; morris water maze; outcome forecast; postnatal; pre-clinical; prenatal; prenatal exposure; response

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.

描述（申请人提供）：婴儿痉挛症属于儿童灾难性癫痫综合征。这些癫痫难以治疗，并且与进行性认知能力下降有关。婴儿痉挛症分为症状性（与诊断的脑部病变相关）或特发性/隐源性（无法揭示病变）。治疗方法是激素治疗，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。目前还没有合适的特发性/隐源性婴儿痉挛动物模型适合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。由于促肾上腺皮质激素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伤可能与建立特发性/隐源性婴儿痉挛症的适当模型有关。我们提出了一种新的婴儿痉挛动物模型，该模型是在产前暴露于倍他米松的大鼠中创建的。出生后全身注射 N-甲基-D-天冬氨酸 (NMDA) 会引发年龄特异性痉挛性癫痫发作。痉挛与婴儿痉挛相似。此外，痉挛期间存在类似于人类电减量反应的脑电图抑制，并且痉挛对 ACTH 治疗敏感。在本提案中，我们将基于产前暴露于倍他米松并在婴儿期使用 NMDA 触发，使用行为和电图癫痫发作、行为/认知结果（水平条、高架十字迷宫、开放场和莫里斯水）来描述特发性/隐源性婴儿痉挛症的新模型迷宫测试）并使用长期脑电图/视频监测筛查自发性癫痫发作的发生。此外，我们将通过使用有效对抗人类婴儿痉挛症的药物（促肾上腺皮质激素、氨己烯酸、泼尼松）及其对开发后期的行为和电图癫痫发作、行为/认知结果和癫痫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，我们将继续根据 NIH 公告 (PAR-06-189) 进行新疗法的临床前开发。婴儿痉挛症是一种毁灭性的儿童癫痫症，尽管接受了治疗，但仍会导致严重的发育衰退。能够改善结果的新有效药物和治疗策略的开发取决于婴儿痉挛症动物模型的可用性。在这里，我们提出了一种新模型，用于研究产前脑损伤后幼年动物引发的婴儿痉挛症。该提案的目的是进一步表征该模型，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该模型。目标是开发足够可靠但相对简单的婴儿痉挛症模型，可用于新的更安全、更有效的治疗方法的常规测试。