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.

本项目的目标是研究5-羟色胺1F(5-HT1F)对线粒体的刺激作用 生物发生(MB)和脊髓损伤(SCI)的恢复。脊髓损伤是一种破坏性的疾病，通常会导致 损伤部位下方功能丧失。虽然与战斗有关的脊柱创伤已经被记录了几个世纪，但在 近年来，服役人员受到了更先进的战争的威胁，比如火箭推进 手榴弹和简易爆炸装置，最终造成更严重和更复杂的伤害，包括 SCI。此外，更重要的是，个人保护、车辆保护和医疗能力的进步 使目前的军事人员得以在过去被证明是致命的伤势中幸存下来。这个 然而，包括脊髓损伤在内的这些伤害的破坏性和衰弱性质并没有减少。这个 退伍军人事务部(VA)是为患有脊髓损伤的个人提供最大的医疗保健网络，提供 照顾美国25%的受害者。慢性阻塞性肺疾病药物治疗的研究进展 脊髓损伤的治疗将极大地造福于患者，也将造福于军队医疗体系。 脊髓损伤的定义是直接损伤脊髓，破坏血管系统，导致氧气减少。 在该区域内传递，并降低线粒体维持细胞能量的能力。神经元性丢失 线粒体的功能最终导致兴奋性毒性和氧化应激，强调了 脊髓损伤后线粒体功能的恢复。有证据表明线粒体功能的恢复 损伤后可以防止进一步的损伤进展，促进恢复。调查研究 线粒体作为脊髓损伤的治疗靶点，仅涉及线粒体功能的个别方面。 事实证明，这在很大程度上是无效的。寻求重建线粒体稳态的治疗学 然而，通过增加MB，脊髓损伤后可以从多个方面缓解损伤进展。 我们的初步数据表明，5-HT1F激动剂诱导幼稚小鼠和 追随SCI。此外，脊髓损伤后每天使用激动剂LY344864治疗的小鼠表现出改善。 线粒体动态平衡，以及损伤体积的减少，以及血管和运动活性的增加 至伤后7天。值得注意的是，LY344864在开始给药1小时或8小时时的疗效相似 后SCI时代。在缺乏5-HT1F受体的小鼠中没有观察到这种效应，这表明 受体是LY344864诱导MB所必需的。Lasmiditan是一种有效和特异的5-HT1F受体激动剂 该公司正在进行偏头痛的第三阶段临床试验。拉西米坦1小时开始治疗 脊髓损伤后也诱导了MB并改善了恢复。我们假设这种治疗方法是 LY344864/Lasmiditan脊髓损伤后将增加MB，从而改善运动恢复和 疼痛反应，减少神经元死亡/功能障碍，增加脊髓损伤后的血管修复。我们 提出以下具体目标：1)确定MB、线粒体稳态(例如，分裂/融合)和 LY344864/Lasmiditan治疗对女性脊髓损伤后功能、运动能力和疼痛的影响 雄性小鼠；2)阐明损伤体积、氧化损伤和神经元凋亡对 LY344864/Lasmiditan在雌性和雄性小鼠脊髓损伤后的研究和3)测定血管恢复和血液-脊髓 LY344864/Lasmiditan脊髓损伤后雌性和雄性小鼠脊髓屏障的完整性 这些研究的成功完成可能揭示5-HT1F受体介导的MB作为一种潜在的治疗策略 脊髓损伤的治疗。此外，拟议的研究将使用一种新的靶点，5-HT1F受体激动剂， 和Lasmiditan，正在进行临床试验，有可能被重新用于治疗 SCI。最后，这些研究将在受伤后8小时开始给药，并在男性和 雌性小鼠，增强临床适用性。