A new animal model of infantile spasms

婴儿痉挛症的新动物模型

• 批准号: 7494013
• 负责人: SOLOMON L. MOSHE
• 金额: $ 21.56万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494013
• 关键词: Age; Age of Onset; Animal Model; Antiepileptic Agents; Behavioral; Biological Models; CRH gene; Central Nervous System Diseases; Cerebrospinal Fluid; Cerebrum; Child; Chronic; Clinic; Cognitive; Collaborations; Condition; Corticotropin; Corticotropin-Releasing Hormone; Data; Development; Developmental Delay Disorders; Disease; Disease regression; Doxorubicin; Educational workshop; Effectiveness; Electroencephalogram; Electroencephalography; Epilepsy; Etiology; Fenclonine; Freedom; Frequencies; Future; Goals; Human; Hypsarrhythmia; Infant; Infantile spasms; Injection of therapeutic agent; Investigational Drugs; Lead; Lesion; Lipopolysaccharides; Magnetic Resonance Imaging; Mental Retardation; Modeling; N-Methylaspartate; NIH Program Announcements; Neonatal; Outcome; Pattern; Phenotype; Process; Rattus; Recurrence; Request for Proposals; Seizures; Serotonin; Spasm; Symptomatic West Syndrome; Syndrome; Therapeutic; Time; Toxin; Translational Research; Treatment Protocols; Triad Acrylic Resin; Validation; Vigabatrin; behavior test; day; design; drug development; experience; improved; infant outcome; innovation; nervous system disorder; outcome forecast; postnatal; pre-clinical; preclinical study; programs; psychosocial; pup; research study; response; white matter

DESCRIPTION (provided by applicant): This application is in response to the NINDS Translational Research Program request for proposals regarding the preclinical development of therapeutics for neurological disorders. Infantile spasms are an age-specific epileptic disorder characterized by repetitive seizures (spasms), specific EEG abnormalities and developmental delay or regression. The long-term outcome is usually catastrophic with a high proportion of children developing mental retardation and chronic epilepsy. The currently available treatments [adrenocorticotropic hormone (ACTH) and vigabatrin] are partly effective but often toxic. Because infantile spasms have such debilitating effects on cognitive development, it is important to develop innovative treatments to stop the seizures and the regression. This will require the identification of a model system to be used to identify candidate therapeutics and to screen for efficacy in preclinical studies. Up to now, there is no such model. Preliminary data suggest that we may have developed a new model of symptomatic infantile spasms. Following injections of three toxins (doxorubicin, lipopolysaccharide, and p- chlorophenylalanine) in the neonatal period, the infant rats experience recurrent spasms over several days associated with ictal seizure discharges resembling in part the EEG features seen in humans including electrodecremental-like responses. Several of the pups will go on to develop partial (limbic) seizures. The pups also show marked deficits in behavioral tests. In this application, we have designed experiments to establish and validate this model. The specific aims are 1) To characterize: A. the behavioral phenotype of the spasms, including age of onset, frequency, clustering and transition from spasms to other seizure types, B. the EEG correlates of the spasms and C. the neurodevelopmental profile of the rats with spasms in terms of acquisition of developmental milestones; and 2. To determine the effectiveness of ACTH and vigabatrin treatment in controlling the spasms both behavioral y and electrogaphically. If successful, our model will satisfy the criteria considered important for the acceptance of a model of infantile spasms by the panelists invited to participate in a NINDS sponsored workshop held in Bethesda, MD on May 13-14, 2004. We have already begun to establish the necessary collaborations to satisfactory complete in the future the drug development process. The establishment and validation of the model may lead to the development of new, effective, therapeutic regimens that can be screened preclinical y and then introduced in the clinic to improve the outcome of infants with this catastrophic condition.

描述（由申请人提供）：此申请响应NINDS转化研究计划的请求，要求有关神经系统疾病治疗的临床前开发的建议。婴儿痉挛是一种年龄特异性的癫痫疾病，其特征是重复性癫痫发作（痉挛），特定的脑电图异常和发育延迟或回归。长期结局通常是灾难性的，患有智力低下和慢性癫痫的儿童比例很高。当前可用的治疗方法[肾上腺皮质激素（ACTH）和Vigabatrin]部分有效，但通常有毒。由于婴儿痉挛对认知发展具有令人衰弱的影响，因此开发创新治疗以阻止癫痫发作和回归很重要。这将需要鉴定模型系统，以识别候选治疗疗法并在临床前研究中筛查功效。到目前为止，还没有这样的模型。初步数据表明，我们可能已经开发了一种新的有症状婴儿痉挛模型。在新生儿时期注射三种毒素（阿霉素，脂多糖和氯苯基丙氨酸）后，婴儿大鼠在几天内经历了复发性痉挛，几天内与Ictal癫痫发作放电相关的部分与某些EEG的特征相关的EEG特征包括人类在内的EEG，其中包括电子持续性响应。几只幼崽将继续发展部分（边缘）癫痫发作。幼崽在行为测试中还显示出明显的缺陷。在此应用程序中，我们设计了实验来建立和验证该模型。具体目的是1）表征：A。痉挛的行为表型，包括发病年龄，频率，聚类和从痉挛到其他癫痫发作类型的过渡，B。和2。确定ACTH和Vigabatrin处理在控制行为Y和电义痉挛方面的有效性。如果成功的话，我们的模型将满足被邀请参加在2004年5月13日至14日在医学博士贝塞斯达举行的NINDS赞助的研讨会的小组成员接受婴儿痉挛模型至关重要的标准。我们已经开始建立必要的合作，以满足未来的药物开发过程。该模型的建立和验证可能会导致开发新的，有效的治疗方案，这些方案可以筛查临床前y，然后在诊所中引入，以改善这种灾难性状况的婴儿的结果。