Infantile Spasms: Molecular Underpinnings of a Novel Combination Therapy

婴儿痉挛症：新型联合疗法的分子基础

• 批准号: 10341168
• 负责人: John William Swann
• 金额: $ 34.67万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341168
• 关键词: 4-Aminobutyrate aminotransferase; Animal Model; Animals; Anticonvulsants; Behavioral; Biological Markers; Birth; Brain; Brain Injuries; Cerebrospinal Fluid; Child; Childhood; Chronic; Clinical; Clinical Research; Combined Modality Therapy; Corticotropin; Development; Disabled Persons; Disease; Electroencephalography; Enzymes; Epilepsy; Event; FDA approved; FRAP1 gene; Gastaut syndrome; Gene Mutation; Glutamates; Glycine; Growth; Hypoxia; Hypsarrhythmia; Impairment; Incidence; Infant; Infantile spasms; Infection; Infusion procedures; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Intellectual functioning disability; Interneurons; Intractable Epilepsy; Knockout Mice; Laboratories; Life; Live Birth; Modeling; Molecular; Neocortex; Nerve; Neurodevelopmental Disorder; Neurologic; Neuropeptides; PI3 gene; Partial Epilepsies; Parvalbumins; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Proline; Proteins; Proto-Oncogene Proteins c-akt; Rattus; Reporting; Role; Signal Pathway; Signal Transduction; Sodium Channel; Spasm; Symptomatic West Syndrome; Synapses; Synaptic Transmission; Testing; Therapeutic; Time; United States; Vigabatrin; Visual Fields; Work; antagonist; conditional knockout; dosage; early childhood; epileptic encephalopathies; experimental study; gamma-Aminobutyric Acid; in vivo; neurodevelopment; new combination therapies; novel; novel therapeutics; postnatal; presynaptic; presynaptic neurons; side effect; suicide substrates; synaptotagmin II; synergism; virtual animals

Infantile spasms is a severe childhood seizure disorder. The incidence is 1 in every 2000 -3000 live births. The spasms are only a few seconds in duration but occur in clusters of up to 100 in a few minutes. The EEG correlates of the disorder are unique. Coincident with each behavioral spasm is a brief ictal event and the interictal EEG is dominated by a chaotic pattern called hypsarrhythmia. The majority of children are intellectually disabled later in life and most of them develop other forms of drug resistant epilepsy. ACTH and vigabatrin can abolish spasms and hypsarrhythmia in 30-80% of patients - depending on the study. However, both drugs can have significant side effects and usually do not prevent the development of the intellectual disabilities and severe epilepsy seen later. Thus better treatments are needed and the hope is that with the advent of relevant animal models, the discovery of underlying mechanisms will lead to new therapies. Our laboratory has developed a model of infantile spasms that recreates the critical features of the disorder. Like infants, the majority of these animals respond to both ACTH and vigabatrin. However, our work has also pointed to a potential new therapy for this disorder. We have found that the expression of Insulin-like Growth Factor -1 (IGF-1) is suppressed in the neocortex of animals with spasms as is signaling through the PI3K-AKT- mTOR growth pathway. At the same time, the expression of parvalbumin and synaptotagmin 2, biomarkers for an important class of inhibitory interneurons and their presynaptic nerve terminals, are also reduced. This has led us to hypothesize that reduced signaling through the PI3K-AKT-mTOR pathway impairs inhibitory interneuron growth which results in an imbalance in synaptic excitation and inhibition and epileptic spasms. Remarkably, treatment with (1-3)IGF-1, a tripeptide derivative of IGF-1, rescues the inhibitory interneurons and abolishes spasms and hypsarrhythmia in over 60% of animals. Moreover, (1-3)IGF-1 dramatically augments the anticonvulsant effects of vigabatrin, reducing the dosage needed to abolish spasms and potentially eliminates its retinotoxicity. This synergy is likely produced by (1-3)IGF-1’s increase in the number of GABAergic nerve terminals and vigabatrin-induced increase in GABA levels in the same synapses. However, very little is known about (1-3)IGF-1 and experiments proposed here focus on understanding its mechanism of action. We plan to test 2 hypotheses. The first is that (1-3)IGF-1 acts through the IGF-1 receptor to activate the PI3K-AKT-mTOR growth pathway. The second is that (1-3)IGF-1 stimulates the growth of parvalbumin interneurons and thereby adds new GABAergic nerve terminals to the neocortex. Lastly, we will attempt to show that (1-3)IGF-1 acts via the IGF-1 receptor when it augments the anticonvulsant effects of vigabatrin. Our results will advance an understanding of the actions of a novel, naturally occurring neuropeptide that likely plays an important roles in neurodevelopment and neurodevelopmental disorders. Moreover, the combination therapy of (1-3)IGF-1 and vigabatrin has significant potential as a better way to treat infantile spasms.

婴儿痉挛是一种严重的童年癫痫发作。该事件每2000-3000个活产中有1个。 痉挛的持续时间仅几秒钟，但在几分钟内最多100群中发生。脑电 该疾病的相关性是独一无二的。与每种行为痉挛的一致是一个简短的无性事件， 发中脑电图以一种称为催眠心律失常的混沌模式为主。大多数儿童是 在以后的生活中，智力残疾，其中大多数发展出其他形式的耐药性癫痫。 acth和 vigabatrin可以在30-80％的患者中消除痉挛和催眠症 - 具体取决于这项研究。然而， 两种药物都可以产生重大副作用，通常不会阻止智力的发展 残疾和严重的癫痫病。需要更好的治疗方法，希望有 相关动物模型的出现，发现潜在机制将导致新疗法。我们的 实验室已经开发了一种基础设施痉挛模型，该模型重现了该疾病的关键特征。喜欢 婴儿，这些动物中的大多数对ACTH和Vigabatrin都反应。但是，我们的工作也有 指出了这种疾病的潜在新疗法。我们发现胰岛素样生长的表达 因子-1（IGF-1）在痉挛的动物的新皮层中被抑制，就像通过pi3k-akt-信号传导 MTOR生长途径。同时，白细胞蛋白和突触毒素2的表达，生物标志物 一类重要的抑制性中间神经元及其突触前神经末端也减少了。这就是 导致我们假设通过PI3K-AKT-MTOR途径减少信号传导会损害抑制 中间神经元的生长导致突触兴奋和抑制和癫痫痉挛的失衡。 值得注意的是，IGF-1的三肽衍生物（1-3）IGF-1处理可挽救抑制性中间神经元和 废除超过60％的动物中的痉挛和催眠症。此外，（1-3）IGF-1急剧增加 Vigabatrin的抗惊厥作用，减少废除痉挛所需的剂量 消除了其视网膜毒性。这种协同作用可能是（1-3）IGF-1的增加数量的增加 GABA能神经末端和Vigabatrin诱导的同一突触中的GABA水平增加。然而， 关于（1-3）IGF-1的知之甚少，此处提出的实验专注于理解其机制 行动。我们计划检验2个假设。首先是（1-3）IGF-1通过IGF-1受体起作用以激活 PI3K-AKT-MTOR生长途径。第二个是（1-3）IGF-1刺激白细胞蛋白的生长 中间神经元，从而在新皮层中添加了新的GABA能神经终端。最后，我们将尝试 表明（1-3）IGF-1通过IGF-1受体起作用，当它增强vigabatrin的抗惊厥作用时。 我们的结果将促进对新颖，自然发生的神经肽的作用的理解 在神经发育和神经发育障碍中起重要作用。而且，组合 （1-3）IGF-1和Vigabatrin的治疗具有重要的潜力，可以作为治疗婴儿痉挛的更好方法。