权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms regulating KCC2 hypofunction during refractory seizures in a mouse model of ischemic neonatal seizures

缺血性新生儿癫痫发作小鼠难治性癫痫发作期间 KCC2 功能低下的调节机制

基本信息

批准号：
10205121
负责人：
Joseph Scafidi
金额：
$ 32.8万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205121
关键词：
Acute Adult Age Agonist Animal Model Anticonvulsants Antiepileptic Agents Basic Science Beds Brain Cells Child Childhood Chlorides Clinical Combined Modality Therapy Data Development Diagnosis Disease Diuretics Dose Down-Regulation Electroencephalogram Electroencephalography Electrophysiology (science)Enhancers Epilepsy Epileptogenesis Etiology Evolution Functional disorder Funding GABA Agonists Goals Grant Harvest Hour Immunohistochemistry Impairment In Vitro Injury Intervention Ischemia Lead Link Mediating Modeling Modification Monitor Mus Neonatal Neonatal Intensive Care Units Neuraxis Neurological outcome Neurons Outcome Pain Disorder Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phenobarbital Phenytoin Physiological Play Predisposition Protein Dephosphorylation Refractory Regulation Reporting Research Research Project Grants Resistance Role Seizures Side Slice Status Epilepticus Syndrome Testing Therapeutic Intervention Up-Regulation Western Blotting Work cell type cognitive disability comorbidity druggable target effective therapy efficacy testing evidence base excitotoxicity experimental study gamma-Aminobutyric Acid improved in vivo in vivo Model innovation mouse model neonatal brain neonatal hypoxic-ischemic brain injury neonatal period neonatal seizure neonate neuropsychiatric disorder novel novel therapeutic intervention novel therapeutics ototoxicity painful neuropathy patch clamp perinatal ischemic stroke power analysis prevent pup response sex side effect small molecule symporter synaptic inhibition trend

项目摘要

Project summary/abstract: The long-term goal of this research project is to gain an understanding of the broader relationship between phenobarbital-resistant seizures in neonates, the role of KCC2 hypofunction in the emergence of refractory seizures, and the efficacy of novel KCC2 functional enhancers in a mouse model of neonatal ischemic seizures. Refractory neonatal seizures are highly correlated with childhood seizure syndromes and cognitive disabilities. The development of more effective therapies will benefit from a deeper understanding of the pathophysiology and mechanisms of underlying refractoriness and epileptogenesis in animal models. The KCC2 chloride co-transporter is the chief Cl- extruder in central nervous system neurons. Severe impairment in a neurons ability to extrude Cl- reverses the transmembrane Cl- gradient resulting in GABA mediated depolarization instead of hyperpolarization. Excitotoxic insults in neonatal brains are often associated with severe seizure burdens that are commonly refractory to first-line therapeutic interventions with GABA agonists like phenobarbital. Our previous work has shown that ischemia significantly downregulates Cl- co-transporter KCC2 expression but NKCC1 expression which is the Cl- importer remains unaffected with trends of upregulation in post-ischemic brains. Rescuing the pathophysiological hypofunction of KCC2 following ischemic insults is an untested strategy in neonatal brains. Hypothesis: Rescuing KCC2 hypofunction in neonatal ischemia will restore the physiological levels of synaptic inhibition and neuronal network activity. This rescue will prevent the emergence of refractory seizures and successfully reduce seizure burdens with GABA agonists which in turn will be disease modifying in the long-term. Aims: 1.Plot the dynamics of early and acute KCC2 degradation following ischemia and investigate the regulation of intrinsic KCC2 hypofunction during ischemic seizures. 2. Document the KCC2 degradation related depolarization of cortical neurons following ischemia and the effects of a KCC2 agonist on such depolarization in-vitro 3. Rescue refractory ischemic - seizures in-vivo with a novel KCC2 agonist and quantitate effect on long-term co-morbidities. Deliverables: Upon successful completion of this project, we will move closer to understanding the link between the dynamic changes of KCC2 expression during neonatal seizures to the emergence of refractoriness. Impact and Innovation: Understanding the mechanisms by which the immature brain is transformed with repeated seizures in the neonatal period will help guide evidence-based strategies into treatments for intractable seizures that are often associated with severe long-term co-morbidities in children.

项目摘要/摘要：这项研究项目的长期目标是了解更广泛的苯巴比妥抵抗的新生儿癫痫发作，KCC2功能低下在难治性发作出现中的作用癫痫发作和新型KCC2功能增强剂对新生儿缺血小鼠模型的疗效癫痫发作。难治性新生儿癫痫与儿童期癫痫综合征和认知功能高度相关残疾人士。更有效的治疗方法的开发将受益于对动物模型中潜在的顽固性和癫痫发生的病理生理学和机制。这个 KCC2氯共转运体是中枢神经系统神经元中主要的氯离子输出器。严重损害神经元排出氯离子的能力逆转了由GABA介导的跨膜氯离子梯度去极化而不是超极化。新生儿大脑中的刺激性侮辱通常与严重的癫痫负担，通常难以通过GABA激动剂进行一线治疗干预比如苯巴比妥。我们以前的工作表明，缺血显著下调了氯-共转运体的表达 KCC2的表达，但NKCC1的表达，作为氯-进口仍然没有受到影响的趋势脑缺血后的上调。抢救KCC2术后病理生理功能减退在新生儿的大脑中，缺血侮辱是一种未经测试的策略。假说：抢救KCC2功能减退新生儿缺血可恢复生理水平的突触抑制和神经元网络活动。这抢救将防止难治性癫痫的出现，并成功减轻GABA的癫痫负担激动剂，从长远来看，将是疾病的改良剂。目标：1.早期和急性的动态布局缺血后KCC2降解及内源性KCC2功能低下的调节缺血性癫痫。2.记录与KCC2降解相关的皮层神经元去极化体外缺血及KCC2激动剂对这种去极化的影响3.抢救难治性缺血一种新型KCC2激动剂的体内癫痫发作和对长期并存疾病的量化影响。交付成果：在这个项目成功完成后，我们将更接近于了解动态新生儿癫痫发作至难治性发作期间KCC2表达的变化影响和创新：了解未成熟的大脑通过重复转化的机制新生儿期的癫痫发作将有助于引导循证策略用于顽固性疾病的治疗癫痫发作通常与儿童严重的长期并存有关。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting ischemia-induced KCC2 hypofunction rescues refractory neonatal seizures and mitigates epileptogenesis in a mouse model.

DOI：
10.1126/scisignal.abg2648
发表时间：
2021-11-09
期刊：
Science signaling
影响因子：
7.3
作者：
Sullivan BJ;Kipnis PA;Carter BM;Shao LR;Kadam SD
通讯作者：
Kadam SD

High Doses of ANA12 Improve Phenobarbital Efficacy in a Model of Neonatal Post-Ischemic Seizures.

高剂量 ANA12 可提高新生儿缺血后癫痫模型中苯巴比妥的疗效。

DOI：
10.3390/ijms25031447
发表时间：
2024
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Vyas,Preeti;Chaturvedi,Ira;Hwang,Yun;Scafidi,Joseph;Kadam,ShilpaD;Stafstrom,CarlE
通讯作者：
Stafstrom,CarlE

Novel Concepts for the Role of Chloride Cotransporters in Refractory Seizures.

氯化物共转运蛋白在难治性癫痫发作中的作用的新颖概念。