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：
9250824
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/9250824
关键词：
Acute Address Adverse effects Affect Animals Anticonvulsants Antiepileptic Agents Binding Brain Chronic Clinical Clinical Treatment Clinical Trials Cognitive Data Data Set Dose Engineering Epilepsy Functional disorder Genetic Glycine Glycine Receptors Goals Grant Hippocampus (Brain)Homeostasis Impaired cognition Kainic Acid Knockout Mice Knowledge Laboratories Modeling Molecular Mus N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurobehavioral Manifestations Outcome Outcome Study Pathway interactions Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Phase II/III Trial Property Recurrence Research Research Proposals Rodent Rodent Model Role Schizophrenia Seizures Site Symptoms Temporal Lobe Epilepsy Testing Therapeutic Therapeutic Studies Viral Vector base behavior test cell type clinical development clinical translation clinically relevant cognitive function cognitive performance 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略了，不仅在我们对病理生理机制的欣赏中，而且在治疗性药物开发工作中同样。该提案基于我们实验室的有希望的初步数据，该数据表明甘氨酸增强药物的抗惊厥作用是前所未有的。具体而言，我们将评估精神分裂症临床发育中的甘氨酸增强药物是否可用于治疗颞叶癫痫（TLE）中的癫痫发作。该赠款将填补知识的关键差距，并提出甘氨酸稳态的破坏与TLE的病理生理有关，并且治疗性甘氨酸增强是治疗TLE的新型药理原理。在海马中，甘氨酸在很大程度上受其特定转运蛋白Glyt1的调节，并履行A 通过与甘氨酸受体（潜在的抗惊厥性）和N-甲基-D-天冬氨酸受体（潜在的预测）结合，作为神经元兴奋性的稳态调节剂。这项面向目标的建议将检验以下中心假设，即治疗性甘氨酸增强代表了颞叶癫痫（TLE）中癫痫发作控制的新策略。我们的初步数据表明，甘氨酸稳态在小鼠TLE模型中受到干扰。此外，我们证明了通过有条件地破坏Glyt1（增加海马甘氨酸）的工程小鼠具有增加的癫痫发作阈值，而Glyt1拮抗剂在小鼠TLE模型中却强得多地抑制了慢性癫痫发作。此外，我们的数据记录了遗传Glyt1破坏的深刻的亲认知作用。测试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，抑制Glyt1的药物，急性癫痫发作和TLE的啮齿动物模型以及相关的行为测试。我们的研究目标将以三个具体目的解决：（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防止啮齿动物癫痫发作的预测。（3）检验以下假设：慢性Glyt1抑制可改善TLE的癫痫发作和认知功能。预期的结果和影响：机械和治疗研究的结合将使我们能够确定Glyt1拮抗剂是否可能是治疗TLE的有用替代药物。我们将对已经在临床试验（II/III期）中测试过的GLYT1抑制剂进行新颖和创新的使用，以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术作为癫痫疗法的新药理原理打开新的机会。治疗性甘氨酸增强的预期益处是癫痫发作控制与亲认知活性相结合，该活性将治疗性甘氨酸增强设置为除了常规的抗癫痫药外，倾向于与认知障碍相关。