Novel presynaptic agents to prevent glutamate-induced neural injury

预防谷氨酸引起的神经损伤的新型突触前药物

• 批准号: 10058292
• 负责人: JEFFREY D ERICKSON
• 金额: $ 32.66万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058292
• 关键词: Acids; Acute; Affect; Affinity; Age; Animal Model; Anticonvulsants; Biochemical; Brain; Central Nervous System Diseases; Chronic; Complementary DNA; Development; Down-Regulation; Electrophysiology (science); Epilepsy; Epileptogenesis; Excitatory Synapse; Exocytosis; Future; Glutamates; Glutamine; Goals; Hippocampus (Brain); Human; In Vitro; Induced Heart Arrest; Intervention; Kainic Acid; Kinetics; Lead; Link; Location; Maintenance; Mediating; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neuroglia; Neurons; Patients; Pharmacology; Plasmids; Presynaptic Terminals; Property; Rattus; Resistance; Resolution; Riluzole; Role; Seizures; Slice; Status Epilepticus; Synapses; System; Temporal Lobe Epilepsy; Testing; Therapeutic; Therapeutic Agents; Traumatic Brain Injury; Western Blotting; alpha ketoglutarate; benzothiazole; excitotoxicity; experimental study; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vitro Assay; in vivo; in vivo Model; knock-down; nerve injury; neuroprotection; neurotransmission; novel; novel therapeutics; presynaptic; prevent; relating to nervous system; side effect; small hairpin RNA; targeted treatment; uptake

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.

颞叶癫痫是最常见的局灶性（部分性）或位置相关性癫痫。 约 60% 的癫痫患者受影响，可发生于任何年龄。 颞叶癫痫极大地促进了对分子、细胞和疾病的理解。 该模型具有神经病理学特征。 颞叶癫痫患者的这种情况有很多潜在的原因，而且往往是确切的原因。 原因尚不清楚，突触前谷氨酸 (Glu) 释放过多会导致 NMDA 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 包括癫痫在内的减少突触 Glu 过度释放的机制可以。 预防/减少对脆弱海马神经元的潜在兴奋性毒性损伤。 防止 Glu 过度释放的方法是有限的，人类研究中的大多数突触后干预措施都是 在正常情况下，由于疗效不佳或不可接受的副作用而令人失望。 囊泡填充所需的突触细胞质 Glu 水平 (~2mM) 通过 α-酮戊二酸衍生的 Glu 拟议项目的科学前提是谷氨酰胺 (Gln) 是 Glu 的前体。 在高突触活性下合成，因为在兴奋活性增加的情况下，谷氨酰胺被输入到轴突中 因此，Na+依赖性谷氨酰胺从神经胶质细胞输入神经元。 在高突触活性下补充突触细胞质 Glu 储备是预防 兴奋毒性条件下过量的谷氨酸释放我们最近发现了神经元活动调节。 在兴奋性突触中表达的谷氨酰胺转运蛋白，可被利鲁唑（一种苯并噻唑）有效抑制 被认为可以抑制突触过度释放谷氨酸的化合物，这是进展的关键障碍。 对涉及过度 Glu 释放的突触前机制的理解一直缺乏分子 有关介导 K+ 刺激、活动调节的 Gln 输入至兴奋性神经的转运蛋白的信息 此外，活性调节的谷氨酰胺转运在突触中支持过量谷氨酸释放的作用。 尚未揭示神经损伤和针对活性调节 Gln 的潜在治疗剂 突触中的运输，具有神经保护作用，更具选择性，具有大脑渗透性，副作用更少 该项目对于推进基础研究具有重要意义。 了解神经元和神经元之间突触过度释放 Glu、Glu/Gln 循环的神经生物学 神经胶质突触和 Glu 诱导的神经元兴奋毒性的解决，为海马神经元突触 Glu 合成中活性调节 Gln 转运的作用提供了基础。 过量 Glu 释放的体外和体内模型，以更好地了解突触前的基本原理 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。