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.

颞叶发作是焦点（部分）或位置相关的偶发性的最常见形式。它 影响所有癫痫患者中约60％，并且可以在任何年龄发生。的海藻酸模型 暂时的叶癫痫大大促成了对分子，细胞和细胞的理解 癫痫发生下的药理机制。该模型具有神经病理学特征 在暂时叶癫痫患者中可以看到。有许多潜在原因，通常是确切的 原因是未知的。突触前谷氨酸（GLU）释放过多会导致NMDA过多的刺激 在许多CNS疾病中实现的受体，导致急性和慢性神经退行性 包括癫痫。在这些条件下减少过量突触GLU释放的机制可能 有可能预防/减少对脆弱海马神经元的兴奋性毒性损害。当前的治疗选择 为了防止过量的GLU释放受到限制，大多数人类研究中的突触后干预措施已经 由于效率差或不可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细胞质GLU水平（〜2mm）是通过α-酮戊二酸GLU 合成。拟议项目的科学前提是谷氨酰胺（GLN）是GLU的先驱 高突触活性下的合成，因为在增加的兴奋活性下GLN被进口到轴突 来自Glia的终端合成。因此，Na+依赖性GLN从GliA到神经元进口到神经元 在高合成活性下，在高合成活性下复制合成细胞质GLU储存是预防的潜在新目标 在兴奋性毒性条件下GLU释放过多。我们最近发现了神经元活性调节 在兴奋性突触中表达的GLN转运蛋白，该突触可能被苯并噻唑riluzole抑制 据信可以抑制突触中过量的GLU释放的化合物。进步的关键障碍 了解过多的GLU释放涉及的突触前机制缺乏分子 有关介导K+刺激，活性调节的GLN导入到兴奋性的转运蛋白的信息 突触。另外，活动调节的GLN转运在突触中的作用支持过量的GLU释放 尚未发现神经损伤和靶向活性GLN的潜在治疗剂 突触中的运输和神经保护性，更具选择性，脑穿透力，副作用较少 尚未开发而不是riluzole。该项目在推进基本方面具有重要意义 了解GLU，GLU/GLN循环神经元与神经元之间的过度突触释放的神经生物学的理解 神经胶质突触和GLU诱导的神经元兴奋毒性。在海马神经元中突触GLU合成中活性调节的GLN转运角色的缺失联系的分辨率为研究提供了研究的基础 体外和体内过量GLU释放的模型，以更好地了解基本突触前 导致突触前GLU诱导的急性和慢性神经退行性疾病的机制。