Characterizing Beta Lactams as Neuroprotectants for Amyotrophic Lateral Sclerosis

表征β内酰胺作为肌萎缩侧索硬化症神经保护剂的作用

• 批准号: 7635845
• 负责人: Jeffrey D Rothstein
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7635845
• 关键词: Amyotrophic Lateral Sclerosis; Animal Model; Animals; Antibiotics; Biological Assay; Brain; Brain Neoplasms; Ceftriaxone; Cerebellar Ataxia; Clinical Trials Design; Data; Disease; Disease Progression; Dose; Drug Kinetics; Drug effect disorder; Epilepsy; Excitatory Amino Acid Transporter 2; FDA approved; Family; Future; GLAST Protein; Gene Expression; Glutamate Transporter; Glutamates; In Vitro; Injury; Lactams; Learning; Life; Measures; Molecular; Monobactams; Motor Neurons; Multiple Sclerosis; Nerve Degeneration; Neurons; Neuroprotective Agents; Onset of illness; Penetration; Pharmaceutical Preparations; Phase; Prosencephalon; Protein Biosynthesis; Proteins; Reporter; Research Personnel; Research Proposals; Rodent; Route; Sampling; Seizures; Spinal Cord; Staging; Time; Tissues; Transgenic Mice; Transgenic Model; Translational Research; Translations; beta-Lactams; follow-up; in vitro Assay; in vitro activity; in vivo; mouse model; muscle strength; neuroprotection; postnatal; programs; promoter; protein expression; tumor growth

The astroglial transporters EAAT1 and EAAT2 are responsible for the largest percentage of glutamate transport in forebrain. Abnormal expression/function of EAAT2 is common to sporadic ALS and to transgenic models of the disease. In addition, altered function of various molecular subtypes of this transporter family is associated with brain tumor growth, cerebellar ataxia, multiple sclerosis and epilepsy. Regulating expression of these proteins could provide powerful therapies to retard disease progression. No practical pharmacological agents exist that can activate glutamate transporters. Studies using EAAT2 transgenic mice recently provide exciting evidence that increasing EAAT2 protein/activity can retard neurodegeneration in ALS animal models; diminish seizures associated with epilepsy, and retard brain tumor growth. A recent NINDS-organized screen of FDA approved drugs, identified beta-lactam antibiotics as modulators of EAAT2. We have accumulated preliminary data that several screened antibiotics can activate EAAT2 gene expression, leading to increased brain protein up to seven fold. The in vitro and in vivo actions of these drugs have been validated- they can protect against excitotoxic injury to cultured neurons/motor neurons. Finally one beta-lactam, ceftriaxone, can delay loss of muscle strength and increase survival in the ALS transgenic mouse model-even when given at disease onset. In this translational research proposal we will systematically evaluate non-antibiotic beta-lactam compounds and beta-lactam antibiotics as modulators of EAAT1 or EAAT2 expression. We will then go on to identify the most potent agent(s) and thoroughly evaluate the drugs in an in vitro-relevant and animal model of ALS. These sequential phases will set the stage for future practical translation towards rational clinical trial design.

星形胶质体转运蛋白EAAT1和EAAT2负责前脑中谷氨酸的最大百分比。 EAAT2的异常表达/功能是零星ALS和疾病的转基因模型的共同点。另外，该转运蛋白家族的各种分子亚型的功能改变与脑肿瘤生长，小脑共济失调，多发性硬化症和癫痫有关。调节这些蛋白质的表达可以为延迟疾病进展提供强大的疗法。没有实用的药理剂可以激活谷氨酸转运蛋白。使用EAAT2转基因小鼠的研究最近提供了令人兴奋的 在ALS动物模型中，增加EAAT2蛋白/活性可以阻止神经退行性的证据；减少与癫痫有关的癫痫发作和延迟脑肿瘤生长。 FDA批准的Ninds组织筛选最近的一个筛查，将β-内酰胺抗生素确定为EAAT2的调节剂。我们积累了初步数据，即几种筛选的抗生素可以激活EAAT2基因的表达，从而导致脑蛋白增加高达7倍。这些药物的体外和体内作用已得到验证 - 它们可以防止对培养的神经元/运动神经元的兴奋性毒性损伤。最终，一个β-内酰胺，头孢曲松，可以延迟损失 肌肉强度并增加ALS转基因小鼠模型的生存，甚至在疾病发作时给予。在这项翻译研究建议中，我们将系统地评估非抗生素β-内酰胺化合物和β-内酰胺抗生素作为EAAT1或EAAT2表达的调节剂。然后，我们将继续识别最有效的药物，并在ALS的体外与动物模型中彻底评估药物。这些顺序阶段将为未来的实用转换奠定阶段，以朝着理性的临床试验设计。