Novel Riluzole Derivatives for Alzheimer's Disease

治疗阿尔茨海默病的新型利鲁唑衍生物

• 批准号: 9979211
• 负责人: JEFFREY D ERICKSON
• 金额: $ 23.7万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979211
• 关键词: Acute; Affinity; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-42; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyotrophic Lateral Sclerosis; Anticonvulsants; Astrocytes; Attenuated; Brain; Chronic; Complement; Dementia; Disease; Dose; Drug Kinetics; Exhibits; FDA approved; Glial Fibrillary Acidic Protein; Gliosis; Glutamate Transporter; Glutamates; Glutamine; Goals; Hippocampus (Brain); Human; Immunohistochemistry; Impaired cognition; Interstitial Lung Diseases; Kinetics; Lead; Learning; Length; Link; Measures; Memantine; Memory; Memory Loss; Modeling; Mus; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Pancreatitis; Penetrance; Peptides; Pharmaceutical Preparations; Pharmacology; Phase II Clinical Trials; Presenile Alzheimer Dementia; Presynaptic Terminals; Production; Property; Protein Precursors; Proteins; Rattus; Riluzole; Rodent Model; Sedation procedure; Senile Plaques; Slice; Synapses; System; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Mice; Transgenic Organisms; Western Blotting; Work; abeta accumulation; abeta oligomer; abnormally phosphorylated tau; benzothiazole; beta amyloid pathology; early onset; entorhinal cortex; excitotoxicity; hippocampal pyramidal neuron; improved; in vivo; inhibitor/antagonist; memory recognition; memory retention; mouse model; mutant; neuron loss; neurotransmission; novel; object recognition; postsynaptic neurons; presenilin; presynaptic; prevent; relating to nervous system; side effect; spatial memory; targeted agent; tau Proteins

ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by progressive memory loss and cognitive decline. Histopathologically, brains of AD patients exhibit an accumulation of amyloid plaques, formed of amyloid β (Aβ) peptides, and of neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein. In the early stages of the disease, enhanced depolarization- stimulated release of glutamate (Glu) and accumulation of Aβ and aberrant tau triggers Glu-induced, NMDA receptor (NMDAR)-dependent excitotoxicity that leads to impaired cognition and eventual neuronal loss. Recent work has revealed that the benzothiazole riluzole prevents age-related cognitive decline in rats and in transgenic mouse models of AD that express mutant human tau or production of toxic Aβ peptides. Riluzole is thought to exert its effects, in part, by reducing activity-stimulated synaptic Glu release. The use of riluzole as a therapeutic agent to limit Glu-induced NMDAR excitotoxicity, however, is limited because riluzole is not very brain penetrant, interacts with multiple pharmacologic targets and causes sedation at higher doses. Excessive and sustained Glu release from synapses triggers NMDA-dependent excitotoxicity in many acute and chronic neurodegenerative conditions. Glu release from synapses must be rapidly recycled to maintain the presynaptic Glu supply for excitatory neurotransmission under high neuronal activity. Glutamine (Gln) released from glia is thought to serve as a precursor for Glu in synaptic terminals under these conditions. We have discovered that neural activity stimulates Gln transport in neurons and that such activity-stimulated Gln transport is coordinately regulated with synaptic Glu release. Interestingly, activity-stimulated Gln transport in pyramidal neurons is one of the most potently inhibited targets of riluzole (IC50 = 1µM). We have developed novel riluzole- derived compounds that are potent inhibitors of activity-stimulated Gln transport and are neuroprotective for this project. Importantly, these compounds are up to 7X more brain penetrant than riluzole, 15X more potent against activity-stimulated Gln transport than other targets of riluzole (e.g., Na+ channel blockade) and therefore are more selective, with potentially fewer side effects. The overall goals of the studies proposed are to 1) test the hypothesis that novel riluzole-derivatives preferentially block activity-stimulated Gln transport and activity-regulated Glu release in mouse hippocampal synapses are more brain penetrant and have longer half- lives than riluzole and 2) test the hypothesis that novel riluzole-derivatives that preferentially block activity- stimulated Gln transport in synapses reduce Aβ load in the entorhinal cortex and hippocampus and attenuate cognitive impairment in a transgenic early-onset AD model (5xFAD mice). Riluzole derivatives that selectively block activity-stimulated Gln transport and reduce Glu-induced/NMDAR-dependent excitotoxicity in hippocampal synapses offer a presynaptic, more brain penetrant and selective therapeutic approach to AD and other related dementias that will complement existing FDA-approved medications (e.g., memantine).

摘要：阿尔茨海默病（AD）是最常见的神经退行性疾病， 进行性记忆丧失和认知能力下降。在组织学上，AD患者的大脑表现出 由淀粉样β（Aβ）肽形成的淀粉样斑块和由神经纤维缠结组成的神经纤维缠结的积累 异常过度磷酸化的tau蛋白在疾病的早期阶段，增强的去极化- 谷氨酸（Glu）的刺激释放和Aβ和异常tau蛋白的积累触发Glu诱导的NMDA 受体（NMDAR）依赖性兴奋性毒性，导致认知受损和最终的神经元损失。 最近的研究表明，苯并噻唑利鲁唑可以预防大鼠和大鼠中与年龄相关的认知能力下降。 AD的转基因小鼠模型，表达突变的人tau蛋白或产生毒性Aβ肽。利鲁唑 被认为部分通过减少活动刺激的突触Glu释放来发挥其作用。使用利鲁唑作为 然而，限制Glu诱导的NMDAR兴奋性毒性的治疗剂是有限的，因为利鲁唑不是非常 脑渗透剂，与多个药理学靶点相互作用，并在较高剂量下引起镇静。过度 在许多急性和慢性神经元损伤中， 神经退行性疾病从突触释放的Glu必须迅速再循环，以维持突触前 高神经元活性下兴奋性神经传递的谷氨酸供应。从神经胶质细胞释放的谷氨酰胺（Gln）是 被认为在这些条件下在突触末梢中充当Glu的前体。我们发现 神经活动刺激神经元中的谷氨酰胺转运，并且这种活动刺激的谷氨酰胺转运 与突触Glu释放协同调节。有趣的是，活动刺激的谷氨酰胺转运在锥体细胞 神经元是利鲁唑最有效的抑制靶点之一（IC 50 = 1µM）。我们开发了一种新的利鲁唑- 衍生的化合物是活性刺激的Gln转运的有效抑制剂， 这个项目重要的是，这些化合物的脑渗透性比利鲁唑高7倍， 与利鲁唑的其他靶点相比，Na+通道阻断）和 因此更有选择性，潜在的副作用更少。拟议研究的总体目标是 1）检验新的利鲁唑衍生物优先阻断活性刺激的Gln转运的假设， 活动调节的小鼠海马突触中的Glu释放更多的脑渗透性，并具有更长的半衰期。 和2）测试优先阻断活性的新型利鲁唑衍生物的假设， 突触中刺激的Gln转运减少内嗅皮层和海马中的Aβ负荷， 在转基因早发性AD模型（5xFAD小鼠）中的认知损害。选择性地 阻断活性刺激的谷氨酰胺转运并减少Glu诱导的/NMDAR依赖的兴奋性毒性， 海马突触为AD提供了一种突触前的、更具脑渗透性和选择性的治疗方法， 将补充现有FDA批准的药物的其他相关痴呆（例如，美金刚）。