Neuroprotective Drugs for Spinal Cord Injury

脊髓损伤的神经保护药物

• 批准号: 6337853
• 负责人: JEAN Rew WRATHALL
• 金额: $ 20.87万
• 依托单位: BIOSTREAM THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-18 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6337853
• 关键词: AMPA receptors; astrocytes; bioengineering /biomedical engineering; biological models; biotechnology; chemoprevention; drug administration rate /duration; drug design /synthesis /production; drug quality /standard; drug screening /evaluation; glutamate receptor; immunocytochemistry; laboratory rat; motor neurons; nervous system disorder chemotherapy; neuropharmacology; neuroprotectants; nonhuman therapy evaluation; oligodendroglia; spinal cord injury; spinal cord surgery; tissue /cell preparation

DESCRIPTION: (Adapted from the Applicant's Abstract) Traumatic spinal cord injury (SCI) leads to permanent loss of motor function and control of function below the level of the injury. A significant portion of the loss is due to secondary factors rather than the initial trauma. These factors include increased extracellular concentrations of glutamate which have demonstrated excitotoxicity. Ionotropic glutamate antagonists, administered acutely after injury showed promise as neuroprotective agents which has not been borne out by clinical trials due to adverse side effects. Recently developed metabotropic glutamate receptor agonists also show neuroprotective characteristics in tissue culture studies and are expected to have a more favorable side effect profile. Preliminary studies of a clinically relevant model of SCI in rodents have adapted it for relatively rapid assay of neuroprotective effects. The present proposal will test 3 of the most promising metabotropic glutamate receptor agonists in this assay and compare them to a known ionotropic glutamate receptor antagonist for neuroprotective effects. Dose response curves at a single time point will be constructed. Then the most efficacious dose of each compound will be tested for therapeutic window after injury. PROPOSED COMMERCIAL APPLICATION: On average, 11,000 traumatic spinal cord injuries (SCI) are reported every year in the United States. Currently, there are no effective medications for the treatment of SCI. The development of effective pharmacotherapies that reduce the severity of injury following a traumatic event could as much as $400 billion on future direct and indirect SCI lifetime costs in the United States alone. The medications developed in this program would also be expected to be efficacious for the treatment of traumatic head injury, stroke and related disorders. STRENGTHS: This is a resubmitted Phase I proposal. The current application has +___________ retained the strengths of the original proposal and corrected the deficiencies noted in the first review. The preliminary studies demonstrate that the 3 drugs to be investigated have shown neuroprotective effects in several different neuronal culture excitotoxicity studies. The present proposal will produce dose response curves for all 3 drugs in comparison with vehicle and with a known neuroprotective ionotropic antagonist. The time of administration will be held at 5 minutes post-injury for all the studies. The use of the ionotropic antagonist for comparison is relevant and useful. A second set of experiments will use the most efficacious dose of each drug and vary the time of delivery post-injury to determine the therapeutic window for administration. The second set of studies do not use strict controls (i.e. administration of vehicle at each time point) but rather use a single group of untreated SCI rats as control. The investigator has justified this control approach by citing previous studies in the laboratory which show no effect of vehicle administration at differing time points. Assessment of neuroprotective capacity will be by determination of numbers of surviving ventral horn motor neurons at lesion site and at discrete distances fore and aft of the site of contusion. Animals will be sacrificed at 24 hours, a time point which has been determined to reflect accurately the level of damage 1 month after injury. Since loss of glia cells has also been associated with loss of function, the investigator will assess numbers of glia, both astrocytes and oligodendrocytes, if time permits. The proposal is well thought out, well written and logical in its flow of experiments. The investigator is well qualified to perform the work. The data from these studies could form the foundation for additional preclinical studies of loss of function in the rodent SCI model and later, human clinical studies. The background and preliminary studies sections suggest that metabotropic glutamate receptor agonists may hold the key to neuroprotection for traumatic injury, inadvertent surgical injury and perhaps neurodegenerative disorders. WEAKNESSES: There are few weaknesses in this application. The investigator +__________ states that the T8 incomplete SCI model induces a respiratory deficit, but this deficit is never explained, nor does it appear to be a measure that will be used to assess loss of function. Clearly, since the accidental mortality in this model is less than 10 percent, the deficit is not lethal. Is it possible to quantify and use this as an assessment of loss of function? Another minor point is that the volume of solution being injected to the injury site is not defined. It is presumed that a single volume will be used and the concentration of drug varied, but this is not spelled out.

描述：（改编自申请人的摘要）创伤性脊髓 伤害（SCI）导致运动功能的永久丧失和功能控制 低于伤害水平。损失的很大一部分是由于 次要因素而不是初始创伤。这些因素包括 谷氨酸的细胞外浓度增加了 兴奋性毒性。离子型谷氨酸拮抗剂，急性施用 受伤表现为神经保护剂的承诺，尚未由 由于不良副作用而进行的临床试验。最近开发了代谢性 谷氨酸受体激动剂还显示了组织中的神经保护特征 培养研究，预计将具有更有利的副作用特征。 啮齿动物中SCI临床相关模型的初步研究具有 对其进行了调整，以相对较快地测定神经保护作用。现在 提案将测试3个最有希望的代谢型谷氨酸受体 该测定中的激动剂并将其与已知的离子谷氨酸进行比较 神经保护作用的受体拮抗剂。剂量反应曲线 将构建单个时间点。然后是最有效的剂量 受伤后将测试化合物的治疗窗口。 拟议的商业应用： 平均每年报告11,000次创伤性脊髓损伤（SCI） 美国。目前，没有有效的治疗药物 科学。开发有效的药物治疗，以减轻严重性 发生创伤事件后的伤害可能多达4000亿美元 仅在美国，间接的SCI寿命成本。开发了药物 在该计划中，也有望有效治疗创伤 头部受伤，中风和相关疾病。 优势：这是一项重新提交的第一阶段建议。当前申请有 +___________ 保留原始提案的优势并纠正了缺陷 在第一次评论中指出。初步研究表明这三种药物 待研究已显示出几种不同的神经保护作用 神经培养兴奋性研究。目前的建议将产生剂量 与车辆相比，所有3种药物的反应曲线以及已知的 神经保护性离子型拮抗剂。管理时间将被持续 在伤害后5分钟进行所有研究。离子型的使用 进行比较的对手是相关且有用的。第二组实验 将使用每种药物的最有效剂量，并改变交货时间 伤害后确定治疗窗口的管理窗口。第二个 一组研究不使用严格的控制（即车辆管理 每个时间点），而是使用一组未处理的科幻大鼠 控制。研究者通过引用这种控制方法是合理的 实验室的先前研究表明车辆没有影响 在不同时间点进行管理。评估神经保护能力 将通过确定在 病变部位，在挫伤部位的离散距离处。 动物将在24小时内牺牲，这是已确定的时间点 为了准确反映受伤后1个月的伤害水平。自从失去 胶质细胞也与功能丧失有关，研究者 如果时间 许可证。 该提议经过深思熟虑，写得很好，逻辑逻辑 实验。研究人员有资格执行这项工作。数据 从这些研究中可以构成其他临床前研究的基础 啮齿动物SCI模型和后来的人类临床研究的功能丧失。 背景和初步研究部分表明代谢性 谷氨酸受体激动剂可以持有神经保护的关键 损伤，无意外科损伤以及神经退行性疾病。 弱点：此应用中很少有弱点。调查员 +__________ 指出T8不完整的SCI模型会引起呼吸不足，但这是 赤字从未解释过，也似乎是一种措施 用于评估功能丧失。显然，由于意外死亡 该模型不到10％，赤字并非致命。是否可以 量化并将其用作功能丧失的评估？另一个未成年人 要点是，注射到伤害部位的溶液量不是 定义。假定将使用单个体积和浓度 药物的多种多样，但这并没有说明。