NKCC1 抑制剂布美他尼作为 TSC 的新型疗法-猫眼课题宝

NKCC1 抑制剂布美他尼作为 TSC 的新型疗法

批准号：

8554384

负责人：

Frances E Jensen

金额：

$18.79万

依托单位：

UNIVERSITY OF PENNSYLVANIA

依托单位国家：

美国

项目类别：

财政年份：

2012

资助国家：

美国

项目状态：

已结题

起止时间：

2012-09-30 至 2015-08-31

来源：

https://reporter.nih.gov/project-details/8554384

关键词：

Address Adjuvant Affect Agonist Animal Model Animals Anticonvulsants Antiepileptic Agents Applications Grants Area Autistic Disorder Benchmarking Biopsy Brain Brain Pathology Bumetanide Cells Child Chloride Ion Chlorides Clinical Cortical Dysplasia Data Disease Diuretics Drug Kinetics Electroencephalography Elements Epilepsy Epileptogenesis Equilibrium Excision Exhibits FDA approved GABA Agonists GABA Receptor Genes Giant Cells Gramicidin Health Henle&apos s loop Hereditary Disease Human In Vitro Incidence Intellectual functioning disability Left Life Measures Mediating Mental Retardation Modeling Morphology Mus Neonatal Neuroglia Neurologic Neurons New Agents Operative Surgical Procedures Outcome Partial Epilepsies Pathway interactions Patients Pharmaceutical Preparations Phase I/II Trial Phenobarbital Population Prevention Publications Rattus Receptor Activation Refractory Relative (related person)Research Resected Resistance Role Safety Sampling Seizures Sirolimus Slice Synapses Techniques Testing Tetanus Helper Peptide Text Tissues Transgenic Mice Tuberous sclerosis protein complex Up-Regulation Validation Vigabatrin Wild Type Mouse Work base clinically relevant gamma-Aminobutyric Acid hippocampal pyramidal neuron human FRAP1 protein human tissue improved in vivo inhibitor/antagonist innovation mTOR Inhibitor mouse model mutant mouse model neonate nestin protein new technology novel novel strategies overexpression pre-clinical preclinical efficacy prevent receptor response sodium-potassium-chloride cotransporter 1 protein therapeutic target treatment strategy

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DESCRIPTION (provided by applicant): This proposal aims to provide preclinical data in support of a novel therapy for epilepsy in Tuberous sclerosis complex (TSC), a disorder that includes early life epilepsy, mental retardation and autism. We propose that bumetanide, an inhibitor of the chloride cotransporter NKCC1, will be effective for the prevention of seizures in TSC alone or in combination with a canonical GABA agonist phenobarbital or the recently approved anticonvulsant vigabatrin. Our recent publication shows that NKCC1 is overexpressed in human TSC tissue, as well as in another cause of refractory epilepsy, focal cortical dysplasia Type IIb (FCD IIb). Increased NKCC1 causes enhanced intracellular chloride, and this impairs inhibitory actions of GABA receptor activation by causing it to mediate depolarization and excitation. We have recently generated a novel Tsc1cc Nestin-rtTA+ tet-OP-cre+ mutant mouse model that is epileptic and shows NKCC1 overexpression and depolarizing GABA responses. Aim 1 will use this mouse model to further text the efficacy of bumetanide alone or in combination with phenobarbital or vigabatrin in cortical slices in vitro and by treatment in vivo using EEG recordings. Aim 2 will examine the effects of bumetanide alone and in combination with phenobarbital or vigabatrin on GABA responses in brain slices acutely prepared from human TSC and FCD IIb surgical biopsy tissue. The proposed work represents a new approach in studying the mechanisms of epileptogenesis in TSC and has the potential to generate an adjuvant novel mechanism-based anticonvulsant strategy for seizure control in TSC patients. It will also provide proof-of-principle for this mechanism, as well as preclinical efficacy in a TSC mouse model with clinically relevant outcomes. Finally our proposal includes target validation as well as mechanism in human tissue. These are critical elements of a path to first-in-human trials for this compound in TSC, and may also extend to FCD IIb.

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