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

本课题的目的是研究5-羟色胺1F（5-HT 1F）对线粒体膜电位的影响， 生物发生（MB）和脊髓损伤（SCI）的恢复。SCI是一种破坏性的疾病， 损伤部位以下的功能丧失。虽然战斗相关的脊柱创伤已经记录了几个世纪， 近年来，服役人员一直受到更先进战争的威胁，如火箭推进的 手榴弹和简易爆炸装置，最终造成更严重和复杂的伤害， SCI.此外，重要的是，个人保护、车辆保护和医疗能力的进步 使现在的军事人员能够在过去被证明是致命的伤害中幸存下来。的 然而，包括SCI在内的这些损伤的破坏性和使人衰弱的性质并未减轻。的 退伍军人事务部（VA）是SCI患者最大的医疗保健网络， 占美国受害者总数的25%。药物治疗的发展 脊髓损伤的治疗不仅对患者，而且对军队医疗系统都有很大的好处。 SCI的定义是脊髓的直接创伤，破坏了血管系统，导致氧气减少 在该区域内递送并降低线粒体维持细胞能量的能力。神经元缺失 线粒体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 可以防止进一步的损伤进展并促进恢复。研究调查 线粒体作为SCI的治疗靶点仅涉及线粒体功能的个别方面 并且被证明是无效的。寻求重建线粒体稳态的治疗 然而，通过增加MB，SCI后可以减轻损伤进展的多个方面。 我们的初步数据表明，5-HT 1F激动剂在未处理小鼠和未处理小鼠的脊髓中诱导MB。 SCI之后。此外，SCI后每天用激动剂LY 344864治疗的小鼠表现出改善的 线粒体稳态，以及减少病变体积，增加血管和运动活性 受伤后7天。值得注意的是，LY 344864在给药后1小时或8小时开始时的疗效相似 SCI后。在缺乏5-HT 1F受体的小鼠中没有观察到这种效应，这表明这种受体的存在可能是一种免疫抑制剂。 受体是LY 344864诱导MB所必需的。Lasmiditan是一种有效的特异性5-HT 1F受体激动剂 正在进行偏头痛的第三阶段临床试验。lasmiditan治疗开始1小时 SCI后也诱导MB并改善恢复。我们假设， SCI后LY 344864/lasmiditan将增加MB，从而改善运动恢复， 疼痛反应，减少神经元死亡/功能障碍和增加SCI后血管修复。我们 提出了以下具体目标：1）确定MB，线粒体稳态（例如裂变/融合）和 SCI后女性对LY 344864/lasmiditan治疗的功能、运动能力和疼痛反应， 雄性小鼠; 2）阐明损伤体积、氧化损伤和神经元凋亡对 3）测定SCI后雌性和雄性小鼠中的血管恢复和血脊髓损伤。 SCI后雌性和雄性小鼠对LY 344864/lasmiditan的脊髓屏障（BSCB）完整性反应 这些研究的成功完成可能揭示5-HT 1F受体介导的MB作为一种潜在的策略， SCI的治疗。此外，拟议的研究将使用一种新的靶点，5-HT 1F受体激动剂， 和lasmiditan，这是正在进行临床试验，并有可能被重新用于治疗 SCI.最后，这些研究将在损伤后8小时开始给药，并在男性和女性中进行。 雌性小鼠，增强临床适用性。

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.