Timing of Neuronal Chloride Uptake for Control of Neonatal Seizure

控制新生儿癫痫发作的神经元氯摄取时机

• 批准号: 10541853
• 负责人: Volodymyr Dzhala
• 金额: $ 40.3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541853
• 关键词: Acute; Admission activity; Anticonvulsants; Antiepileptic Agents; Astrocytes; Biological Assay; Blood - brain barrier anatomy; Brain; Brain Hypoxia-Ischemia; Carotid Arteries; Cations; Cell Volumes; Cells; Cerebral Palsy; Child; Chlorides; Chronic; Circulation; Cytoplasm; Data; Drug Targeting; Early treatment; Edema; Epilepsy; Epileptogenesis; Glucose; Goals; Hippocampus; Hour; Human; Image; In Vitro; Incidence; Injury; Interneurons; Ischemia; Ligation; LoxP-flanked allele; Measurement; Measures; Membrane; Modeling; Monitor; Mus; Neonatal; Neuronal Injury; Neurons; Newborn Infant; Outcome; Oxygen; Pathway interactions; Perfusion; Perinatal Hypoxia; Permeability; Potassium; Potassium Chloride; Preparation; Prevention; Process; Pyramidal Cells; Randomized; Recovery; Recurrence; Regulation; Reperfusion Therapy; Resistance; Role; Salts; Seizures; Severities; Signal Transduction; Sodium Chloride; Swelling; Testing; Therapeutic; Tissues; Transgenic Organisms; Water; cell injury; cell type; clomeleon; cytotoxic; deprivation; disability; experimental study; extracellular; fluorescence lifetime imaging; fluorophore; gamma-Aminobutyric Acid; high risk; hypoxic ischemic injury; improved; in vivo; inhibitor; multiphoton microscopy; neonatal human; neonatal hypoxic-ischemic brain injury; neonatal injury; neonatal seizure; neonate; postsynaptic; prevent; ratiometric; receptor; receptor-mediated signaling; sodium-potassium-chloride cotransporter 1 protein; spreading depression; symporter; synaptic inhibition; therapeutically effective; treatment strategy; two photon microscopy; two-photon; uptake

Project Summary and Abstract Neuronal chloride concentration ([Cl-]i) is an important determinant of both post-synaptic GABAA- receptor mediated signaling and cell volume regulation. After injury, neurons swell by admitting water and chloride salts. The chloride moiety alters the reversal potential for GABA signaling, compromising inhibition and contributing to early anticonvulsant-resistant seizures that are thought to worsen long- term outcomes. An important pathway for neuronal entry of water and chloride salts are the reversible cation-Cl- cotransporters (CCC) NKCC1 and KCC2. We hypothesize that emergent limitation of neuronal chloride influx after recovery from hypoxia-ischemia by antagonizing NKCC1 activity and/or KCC2 activity is a uniquely effective therapeutic strategy to reduce acute cell swelling and [Cl-]i elevation in injured neurons, restore GABAergic inhibition, prevent chronic [Cl-]i elevation, recurrent seizures and epileptogenesis. We will test these hypotheses in vitro and in vivo using established models of hypoxic ischemic injury, transgenic chloride imaging, and multiphoton microscopy. The overall goal of this project is to elucidate the progressive role of cation-chloride transport activity in hypoxia-ischemia induced neuronal injury and seizures. The results will have an important positive impact immediately because they will identify an optimal therapeutic window for prevention and treatment of recurrent seizures in newborns that have suffered hypoxia-ischemia and are at high risk for developing anticonvulsant resistant seizures, epilepsy, cerebral palsy and neuromotor disabilities.

项目摘要和摘要 神经元氯化物浓度（[Cl-] I）是两种突触后Gabaa-的重要决定因素 受体介导的信号传导和细胞体积调节。受伤后，神经元通过接受水肿胀 和氯化盐。氯化部分改变了GABA信号的逆转潜力，损害 抑制作用并导致早期抗惊厥性癫痫发作，被认为会恶化长期 术语成果。水和氯化盐的神经元进入的重要途径是可逆的 阳离子 - 共转运剂（CCC）NKCC1和KCC2。我们假设对 通过对NKCC1活性和/或 KCC2活性是减少急性细胞肿胀和[Cl-] I的独特有效的治疗策略 受伤的神经元的抬高，恢复GABA能抑制，防止慢性[Cl-] I高升高，反复发作 癫痫发作和癫痫发生。我们将使用已建立的体外和体内测试这些假设 低氧缺血性损伤，转基因氯化成像和多光子显微镜的模型。这 该项目的总体目标是阐明阳离子 - 氯化物运输活动的渐进作用 缺氧 - 缺血性诱导神经元损伤和癫痫发作。结果将具有重要的积极 立即影响，因为他们将确定预防和 治疗患有缺氧性缺血并处于高风险的新生儿中的复发性癫痫发作 为了形成抗惊厥性癫痫发作，癫痫，脑瘫和神经运动障碍。