Novel presynaptic agents to prevent glutamate-induced neural injury

颞叶癫痫是局灶性(部分)或局部性癫痫最常见的形式。它 影响约60%的癫痫患者，可发生在任何年龄。红藻氨酸模型 颞叶癫痫极大地促进了对分子、细胞和 癫痫发生的药理机制。该模型具有神经病理特征。 可见于颞叶癫痫患者。有许多潜在的原因，而且通常是确切的 原因不明。突触前谷氨酸(Glu)的过度释放导致NMDA的过度刺激 与许多导致急性和慢性神经变性的中枢神经系统疾病有关的受体 包括癫痫。在这些情况下减少过度突触Glu释放的机制可能 潜在地预防/减少对脆弱的海马神经元的兴奋性毒性损伤。当前的治疗方案 防止谷氨酸过度释放的方法是有限的，大多数人类研究中的突触后干预措施 由于疗效不佳或不能接受的副作用而令人失望。在正常情况下，维护 囊泡填充所需的突触胞质Glu水平(~2 mM)是通过α-酮戊二酸衍生的Glu实现的 综合。拟议项目的科学前提是谷氨酰胺(Gln)是谷氨酸的前体 高突触活性下的合成，因为在兴奋活性增加的情况下，谷氨酰胺被输入到轴突 胶质细胞的末端，在那里它被合成。因此，钠离子依赖的谷氨酸氨基转移到神经元，从胶质细胞到 在高突触活动下补充突触胞浆中的谷氨酸是一个潜在的新靶点 在兴奋性毒性条件下过量释放谷氨酸。我们最近发现了一种神经元活动受调节 谷氨酰胺转运体在兴奋性突触中的表达，而利鲁唑可有效地抑制这种突触 一种被认为能抑制突触过度释放谷氨酸的化合物。取得进展的关键障碍 对谷氨酸过度释放所涉及的突触前机制的了解一直缺乏分子基础 介导K+刺激、活性调节的谷氨酰胺进入兴奋性的转运体的信息 突触。此外，突触中活性调节的谷氨酸氨基转移支持谷氨酸过度释放的作用 神经损伤和潜在的针对活动调节的谷氨酰胺的治疗药物尚未被揭示 在突触中运输，具有神经保护作用，更具选择性，更具脑穿透性，副作用更少 而利鲁唑还没有被开发出来。该项目对推进基础设施建设具有重要意义。 神经元与神经细胞间Glu、Glu/Gln循环突触过度释放的神经生物学研究 神经胶质突触和谷氨酸诱导的神经元兴奋性毒性。解决海马神经元中活性调节的谷氨酰胺转运在突触谷氨酸合成中所起的作用这一缺失环节的解决为研究 体外和体内谷氨酸过度释放模型以更好地了解基本的突触前 导致突触前谷氨酸诱导的急性和慢性神经退行性疾病的机制。

Temporal lobe epilepsy is the most common form of focal (partial) or location related epilepsy. It affects about 60 percent of all people with epilepsy and can occur at any age. The kainic acid model of temporal lobe epilepsy has greatly contributed to the understanding of the molecular, cellular and pharmacological mechanisms underlying epileptogenesis. This model presents with neuropathological features that are seen in patients with temporal lobe epilepsy. There are many potential causes, and often the exact cause is unknown. Excessive presynaptic glutamate (Glu) release causes excessive stimulation of NMDA receptors that is implicated in many CNS disorders that result in acute and chronic neurodegeneration including epilepsy. Mechanisms to reduce excessive synaptic Glu release under these conditions could potentially prevent/reduce excitotoxic damage to vulnerable hippocampal neurons. Current treatment options to prevent excessive Glu release are limited and most post-synaptic interventions in human studies have been disappointing because of poor efficacy or unacceptable side effects. Under normal conditions, maintenance of synaptic cytoplasmic Glu levels (~2mM) required for vesicular filling is via α-ketoglutarate-derived Glu synthesis. The scientific premise for the proposed project is that glutamine (Gln) is a precursor for Glu synthesis under high synaptic activity because under increased excitatory activity Gln is imported into axon terminals from glia where it is synthesized. Hence, Na+-dependent Gln import into neurons from glia to replenish synaptic cytoplasmic Glu stores under high synaptic activity is a potential novel target to prevent excessive Glu release under excitotoxic conditions. We have recently discovered a neuronal activity-regulated Gln transporter expressed in excitatory synapses that is potently inhibited by riluzole, a benzothiazole compound that is believed to inhibit excessive Glu release from synapses. A critical barrier to progress in understanding the presynaptic mechanisms involved in excessive Glu release has been the lack of molecular information about the transporter that mediates K+-stimulated, activity-regulated Gln import into excitatory synapses. In addition, the role of activity-regulated Gln transport in synapses to support excessive Glu release and neural injury has not been revealed and potential therapeutic agents that target activity-regulated Gln transport in synapses and that are neuroprotective, more selective, brain penetrant, with fewer side effects than riluzole have not been developed. This project has important implications in advancing basic understanding of the neurobiology of excessive synaptic release of Glu, Glu/Gln cycling between neuronal and glial synapses, and Glu-induced neuronal excitotoxicity. Resolution of this missing link of the role for activity-regulated Gln transport in synaptic Glu synthesis in hippocampal neurons provide the basis for studies in in vitro and in vivo models of excessive Glu release to better understand the fundamental presynaptic mechanisms that lead to presynaptic Glu-induced acute and chronic neurodegenerative diseases.