5-HT1F receptor agonism as a novel therapeutic strategy following spinal cord injury

5-HT1F 受体激动剂作为脊髓损伤后的新型治疗策略

• 批准号: 10300436
• 负责人: Rick G Schnellmann
• 金额: --
• 依托单位: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-11-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300436
• 关键词: Address; Advocate; Age; Agonist; American; Animal Model; Area; Biogenesis; Biology; Blood; Blood Vessels; Caregivers; Caring; Clinical; Clinical Trials; Complex; Conflict (Psychology); Data; Development; Devices; Disease; Doctor of Philosophy; Event; Exhibits; Female; Financial compensation; Freedom; Functional disorder; Goals; Health Care Costs; Healthcare; Healthcare Systems; Homeostasis; Human; Human Resources; Individual; Injury; Institution; Intensive Care; Knockout Mice; Lesion; Locomotor Recovery; Mediating; Mediator of activation protein; Medical; Migraine; Military Personnel; Mitochondria; Motor Activity; Mus; Natural regeneration; Nature; Neurosurgeon; Oxidants; Oxidative Stress; Oxygen; Pain; Paralysed; Pathologic; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phase III Clinical Trials; Recovery; Rehabilitation therapy; Secondary to; Serotonin; Site; Spinal Cord; Spinal cord injury; Therapeutic; Time; Tissues; Trauma; United States; United States Department of Veterans Affairs; Veterans; care costs; clinical application; combat; disability; drug discovery; excitotoxicity; experience; improved; innovation; life time cost; loss of function; male; mitochondrial dysfunction; neuron apoptosis; neuron loss; novel; novel therapeutic intervention; operation; oxidative damage; patient population; programs; receptor; repair function; repaired; response; restoration; serotonin receptor; service member; spinal cord repair; therapeutic target

The goal of this project is to study the 5-hydroxytryptamine 1F (5-HT1F) in stimulating mitochondrial biogenesis (MB) and recovery from spinal cord injury (SCI). SCI is a devastating disorder often resulting in loss of function below the injury site. While combat-related spinal trauma has been documented for centuries, in recent years, service members have been threatened by more advanced warfare, such as rocket-propelled grenades and improvised explosive devices, ultimately inducing more severe and complex injuries, including SCI. Further, and importantly, advancements in personal protection, vehicular protection and medical capabilities have allowed current military personnel to survive injuries that would have proven lethal in the past. The devastating and debilitating nature of these injuries, however, including SCI, has not been lessened. The Department of Veterans Affairs (VA) is the largest healthcare network for individuals suffering from SCI, providing care for 25% of total victims in the United States. The development of pharmacological therapeutics for the treatment of SCI would greatly benefit not only sufferers, but also the military healthcare system. SCI is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen delivery within the area and reducing the ability of mitochondria to maintain cellular energetics. Neuronal loss of mitochondrial function ultimately leads to excitotoxicity and oxidative stress, emphasizing the critical nature of restoration of mitochondrial function following SCI. Evidence suggests that restoration of mitochondrial function after injury could protect against further injury progression and enhance recovery. Studies investigating mitochondria as a therapeutic target for SCI have only addressed individual aspects of mitochondrial function and have proven largely inefficacious. Therapeutics pursuing reestablishment of mitochondrial homeostasis through increased MB, however, following SCI could alleviate multiple facets of injury progression. Our preliminary data indicate that the 5-HT1F agonism induces MB in the spinal cord of both naïve mice and following SCI. Additionally, mice treated daily with the agonist LY344864 following SCI exhibited improved mitochondrial homeostasis, as well as decreased lesion volume, and increased vascular and locomotor activity by 7 days post-injury. Remarkably, LY344864 efficacy was similar when administration was initiated 1 or 8 h post-SCI. This effect was not observed in mice lacking the 5-HT1F receptor, indicating that the presence of this receptor is necessary for LY344864-induced MB. Lasmiditan is a potent and specific 5-HT1F receptor agonist that is undergoing phase III clinical trials for migraine headaches. Treatment with lasmiditan beginning 1 h post-SCI also induced MB and improved recovery. We hypothesize that treatment with LY344864/lasmiditan following SCI will increase MB, resulting in improved locomotor recovery and pain response, decreased neuronal death/dysfunction and increased vascular repair post-SCI. We propose the following Specific Aims: 1) Determine MB, mitochondrial homeostasis (e.g. fission/fusion) and function, locomotor capability and pain in response to LY344864/lasmiditan treatment post-SCI in female and male mice; 2) Elucidate lesion volume, oxidative damage, and neuronal apoptosis in response to LY344864/lasmiditan post-SCI in female and male mice and 3) Determine vascular recovery and blood-spinal cord barrier (BSCB) integrity in response to LY344864/lasmiditan post-SCI in female and male mice Successful completion of these studies could unveil 5-HT1F receptor-mediated MB as a potential strategy for therapeutic treatment of SCI. Additionally, the proposed study will use a novel target, 5-HT1F receptor agonism, and lasmiditan, which is undergoing clinical trials and has the potential to be repurposed for the treatment of SCI. Finally, these studies will initiate drug administration 8 h after injury and be performed in both male and female mice, strengthening clinical applicability.

该项目的目的是研究5-羟色胺1F（5-HT1F）刺激线粒体 生物发生（MB）和脊髓损伤（SCI）的恢复。 SCI是一种毁灭性疾病，通常导致 受伤部位下方的功能丧失。虽然已经记录了与战斗有关的脊柱创伤已有数百年的历史 近年来，服务成员受到更高级战争的威胁，例如火箭推荐 手榴弹和改进的爆炸装置，最终诱发了更严重和复杂的伤害，包括 科学。此外，重要的是，个人保护，车辆保护和医疗能力方面的进步 允许目前的军事人员在过去证明致命的伤害中生存。 然而，包括SCI在内的这些伤害的毁灭性和使人衰弱的性质并没有减少。这 退伍军人事务部（VA）是针对患有SCI的个人的最大医疗网络，提供 照顾美国的25％的受害者。开发药物治疗 SCI的治疗不仅会使患者，而且会使军事保健系统受益。 SCI是通过直接创伤对脊髓的直接创伤来定义的，脊髓破坏了脉管系统，导致氧气减少 在该区域内递送并降低线粒体维持细胞能的能力。神经元丧失 线粒体功能最终导致兴奋性和氧化应激，强调 SCI后线粒体功能的恢复。有证据表明线粒体功能的恢复 受伤后可以防止进一步的伤害进展并增强康复。研究调查 线粒体作为SCI的治疗靶标仅针对线粒体功能的各个方面 并证明很大程度上是不足的。追求重新建立线粒体稳态的治疗剂 但是，通过增加MB，SCI之后可以减轻损伤进展的多个方面。 我们的初步数据表明5-HT1F激动剂在幼稚小鼠和 跟随科学。此外，SCI暴露后，每天用激动剂LY344864治疗的小鼠改善 线粒体稳态，以及改善的病变体积，增加血管和运动活性 受伤后7天。值得注意的是，当启动1或8 h时，LY344864效率相似 sci。在缺乏5-HT1F受体的小鼠中未观察到这种作用，表明存在这种效果 受体是LY344864诱导的MB所必需的。 lasmiditan是一种潜力和特定的5-HT1F受体激动剂 这正在进行III期偏头痛标头的临床试验。从1小时开始用lasmiditan治疗 SCI后还诱导MB并改善恢复。我们假设用 SCI后LY344864/LASMIDITAN将增加MB，从而改善运动能力恢复和 SCI后疼痛反应，神经元死亡/功能障碍减少和血管修复增加。我们 建议以下具体目的：1）确定MB，线粒体稳态（例如裂变/融合）和 在女性和SCI后，对LY344864/LASMIDITAN治疗的功能，运动能力和疼痛 雄性老鼠； 2）阐明病变体积，氧化损伤和神经元凋亡 LY344864/雌性和雄性小鼠的lastiditan后-SCI，3）确定血管恢复和血统 响应于ly344864/lasmiditan post-sci的脐带屏障（BSCB）完整性 这些研究的成功完成可以公布5-HT1F受体介导的MB，作为潜在的策略 科学治疗。此外，拟议的研究将使用新的靶标5-HT1F受体激动剂， 和Lasmiditan，正在进行临床试验，并有可能重新使用以治疗 科学。最后，这些研究将在受伤后8小时启动药物管理，并在男性和 雌性小鼠，增强临床适用性。