Glycine augmentation therapy for the treatment of epilepsy

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理解中，而且在治疗药物开发工作中也是如此。这一建议是基于我们实验室的有希望的初步数据，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。具体来说，我们将评估是否甘氨酸增强药物，这是已经在临床开发的精神分裂症，可用于治疗癫痫发作的颞叶癫痫（TLE）。这项资助将填补知识的关键空白，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理。在海马体中，甘氨酸在很大程度上受其特异性转运蛋白GlyT 1的调节，并实现了对海马体的免疫调节。 通过结合甘氨酸受体（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），作为神经元兴奋性的稳态调节剂的双重作用。这个目标导向的建议将测试中央假设，治疗性甘氨酸增强是一种新的策略，颞叶癫痫（TLE）发作控制。我们的初步数据表明，甘氨酸稳态在TLE小鼠模型中受到干扰。此外，我们证明了GlyT 1有条件破坏（以增加海马甘氨酸）的工程小鼠癫痫发作阈值增加，而GlyT 1拮抗剂在TLE小鼠模型中强烈抑制慢性癫痫发作。此外，我们的数据记录了遗传GlyT 1破坏的深刻的促认知作用。测试我们的假设所需的关键实验工具包括破坏GlyT 1功能的遗传工具、GlyT 1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。本研究的主要目的有三：（1）明确甘氨酸抑制癫痫发作的机制。(2)测试急性甘氨酸增强预防啮齿动物癫痫发作的预测。(3)测试慢性GlyT 1抑制改善TLE癫痫发作和认知功能的假设。预期成果和影响：机制和治疗研究的结合将使我们能够确定GlyT 1拮抗剂是否可能是治疗TLE的有用的替代药物。我们将利用已经在临床试验（II/III期）中测试的GlyT 1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型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获益是癫痫发作控制与促认知活性相结合，这将治疗性甘氨酸增强与传统抗癫痫药物区分开来，传统抗癫痫药物往往与认知障碍相关，这是一种显著的副作用。

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.