Glycine augmentation therapy for the treatment of epilepsy

描述(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了，不仅在我们对病理生理机制的认识上，而且在治疗药物开发努力中也是如此。这一建议是基于我们实验室有希望的初步数据，这些数据表明甘氨酸增强药物具有前所未有的抗惊厥作用。具体地说，我们将评估已经在精神分裂症临床开发中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。这项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，治疗性甘氨酸增强是治疗TLE的一种新的药理学原则。在海马区，甘氨酸在很大程度上受其特定的转运体GlyT1的调节，并满足 通过结合甘氨酸受体(潜在的抗惊厥作用)和N-甲基-D-天冬氨酸受体的甘氨酸B位点(潜在的先知性)，作为神经元兴奋性的动态平衡调节的双重作用。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)发作控制的新策略。我们的初步数据表明，甘氨酸稳态在TLE小鼠模型中被扰乱。此外，我们还证明，在TLE小鼠模型中，条件阻断GlyT1(增加海马区甘氨酸)的工程小鼠可以提高癫痫阈值，而GlyT1拮抗剂则有力地抑制了慢性癫痫发作。此外，我们的数据证明了遗传GlyT1中断对认知的深刻影响。检验我们的假说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。我们的研究目标将集中在三个具体目标上：(1)确定甘氨酸抑制癫痫发作的机制。(2)验证急性甘氨酸增加预防啮齿类动物癫痫发作的预测。(3)验证慢性GlyT1抑制改善TLE患者癫痫发作和认知功能的假说。预期结果和影响：机制研究和治疗性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。我们将创新地使用已经在临床试验(II/III期)中测试的GlyT1抑制剂来治疗精神分裂症的认知症状。现有药物的新的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则的临床翻译打开新的机会。治疗性甘氨酸增强的预期好处是癫痫控制和促进认知的活动相结合，这使得治疗性甘氨酸增强有别于传统的抗癫痫药物，后者往往与认知障碍有关，是显著的副作用。

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.