Glycine augmentation therapy for the treatment of epilepsy

甘氨酸增强疗法治疗癫痫

基本信息

批准号：
8753797
负责人：
Detlev Boison
金额：
$ 36.09万
依托单位：
LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8753797
关键词：
Acute Address Adverse effects Affect Animals Anticonvulsants Antiepileptic Agents Binding Brain Chronic Clinical Clinical Treatment Clinical Trials Cognitive Data Data Set Development Dose Engineering Epilepsy Functional disorder Genetic Glycine Glycine Receptors Goals Grant Hippocampus (Brain)Homeostasis Impaired cognition Kainic Acid Kindling (Neurology)Knockout Mice Knowledge Laboratories Mining Modeling Molecular Mus N-Methyl-D-Aspartate Receptors Neurobehavioral Manifestations Outcome Outcome Study Pathway interactions Performance Pharmaceutical Preparations Phase II/III Trial Property Recurrence Research Research Proposals Rodent Rodent Model Role Schizophrenia Seizures Site Symptoms Tars Temporal Lobe Epilepsy Testing Therapeutic Therapeutic Studies Translations Viral Vector base behavior test cell type clinically relevant cognitive function drug development improved inhibitor/antagonist innovation mouse model neglect neuronal excitability novel novel strategies novel therapeutics pre-clinical prevent public health relevance tool

项目摘要

DESCRIPTION (provided by applicant): The role of glycine homeostasis in epilepsy has largely been neglected, not only in our appreciation of pathophysiological mechanisms, but likewise in therapeutic drug development efforts. This proposal is based on promising preliminary data from our laboratory, which demonstrate an unprecedented anticonvulsant role of glycine augmenting drugs. Specifically, we will evaluate whether glycine augmenting drugs, which are already in clinical development for schizophrenia, could be used for the treatment of seizures in temporal lobe epilepsy (TLE). This grant will fill a critical gap in knowledge and proposes that disruption of glycine homeostasis is implicated in the pathophysiology of TLE and that therapeutic glycine augmentation is a novel pharmacological principle for the treatment of TLE. In hippocampus, glycine is largely regulated by its specific transporter GlyT1, and fulfills a dual role as homeostatic regulator of neuronal excitability by binding to glycine receptors (potentially anticonvulsive) and the glycineB-site of N-methyl-D-aspartate receptors (potentially procognitive). This goal-oriented proposal will test the CENTRAL HYPOTHESIS that therapeutic glycine augmentation represents a novel strategy for seizure control in temporal lobe epilepsy (TLE). Our preliminary data demonstrate that glycine homeostasis is perturbed in a mouse model of TLE. Further, we demonstrated that engineered mice with conditional disruption of GlyT1 (to increase hippocampal glycine) have increased seizure thresholds, whereas a GlyT1 antagonist robustly suppressed chronic seizures in a mouse model of TLE. In addition, our data document a profound pro-cognitive effect of genetic GlyT1 disruption. Key experimental tools required to test our hypothesis include genetic tools to disrupt GlyT1 function, GlyT1-inhibiting drugs, rodent models of acute seizures and of TLE, and relevant behavioral tests. Our research goals will be addressed in three Specific Aims: (1) Identify the mechanisms of seizure suppression by glycine. (2) Test the prediction that acute glycine augmentation prevents seizures in rodents. (3) Test the hypothesis that chronic GlyT1 inhibition improves seizures and cognitive function in TLE. Expected outcome and impact: A combination of mechanistic and therapeutic studies will allow us to determine whether GlyT1 antagonists might be useful alternative drugs for the treatment of TLE. We will make novel and innovative use of GlyT1 inhibitors that have already been tested in clinical trials (phase II/III) to treat cognitive symptms in schizophrenia. Identification and characterization of a novel anticonvulsant role of existing drugs will open new opportunities for clinical translation of therapeutic glycine augmentation as novel pharmacological principle for epilepsy therapy. The expected benefit of therapeutic glycine augmentation is seizure control combined with a pro-cognitive activity, which sets therapeutic glycine augmentation apart from conventional antiepileptic drugs, which tend to be associated with cognitive impairment as prominent side effect.

描述（由申请人提供）：甘氨酸稳态在癫痫中的作用在很大程度上被忽视，不仅在我们对病理生理机制的认识中，而且在治疗药物开发工作中也是如此。该提议基于我们实验室的有希望的初步数据，这些数据证明了甘氨酸增强药物具有前所未有的抗惊厥作用。具体来说，我们将评估已经处于精神分裂症临床开发阶段的甘氨酸增强药物是否可以用于治疗颞叶癫痫（TLE）的癫痫发作。这笔资助将填补一个关键的知识空白，并提出甘氨酸稳态的破坏与 TLE 的病理生理学有关，并且治疗性甘氨酸增强是治疗 TLE 的新药理学原理。在海马体中，甘氨酸很大程度上受其特定转运蛋白 GlyT1 的调节，并履行通过与甘氨酸受体（潜在抗惊厥）和 N-甲基-D-天冬氨酸受体的甘氨酸 B 位点（潜在促认知）结合，发挥神经元兴奋性稳态调节剂的双重作用。这项以目标为导向的提案将检验中心假设，即治疗性甘氨酸增强代表了颞叶癫痫 (TLE) 癫痫发作控制的新策略。我们的初步数据表明，TLE 小鼠模型中的甘氨酸稳态受到干扰。此外，我们还证明，条件性破坏 GlyT1（以增加海马甘氨酸）的工程小鼠的癫痫阈值有所增加，而 GlyT1 拮抗剂则可有效抑制 TLE 小鼠模型中的慢性癫痫发作。此外，我们的数据记录了基因 GlyT1 破坏对认知的深远影响。检验我们的假设所需的关键实验工具包括破坏 GlyT1 功能的遗传工具、GlyT1 抑制药物、急性癫痫发作和 TLE 的啮齿动物模型以及相关的行为测试。我们的研究目标将通过三个具体目标来实现：（1）确定甘氨酸抑制癫痫发作的机制。 (2) 测试急性甘氨酸增强可预防啮齿类动物癫痫发作的预测。 (3) 检验慢性 GlyT1 抑制可改善 TLE 癫痫发作和认知功能的假设。预期结果和影响：机制研究和治疗研究的结合将使我们能够确定 GlyT1 拮抗剂是否可能成为治疗 TLE 的有用替代药物。我们将创新性地使用已经在临床试验（II/III 期）中进行测试的 GlyT1 抑制剂来治疗精神分裂症的认知症状。现有药物的新型抗惊厥作用的鉴定和表征将为治疗性甘氨酸增强作为癫痫治疗的新药理学原理的临床转化开辟新的机会。治疗性甘氨酸增强的预期益处是癫痫发作控制与促认知活性相结合，这使得治疗性甘氨酸增强与传统抗癫痫药物不同，传统抗癫痫药物往往与认知障碍作为显着副作用相关。