Efficacy and safety of a new hexadentate iron chelator therapy for TBI-induced chronic disabilities in a rodent model

创伤性脑损伤(TBI)护理和康复是当前和未来的重大挑战 退伍军人健康系统(VHS)。除了特定的残疾外，人们越来越担心特发性脑损伤可能 显著增加长期慢性炎症诱发进展性疾病的风险因素。目前， 解决这两个问题的有效疗法因缺乏足够的神经生物学而受到阻碍。 指导改进残疾治疗和慢性病预防战略的基金会。 加减速颅脑损伤导致微血管剪切损伤、血脑屏障(BBB)功能障碍 微量出血。弥漫性微出血沉积的铁通过活性氧物种助燃炎症 (ROS)和其他炎症途径可能进一步导致进行性残疾。有迫切的需要 解决特定残疾和长期进展性疾病的风险因素，并制定有效的 具有极好的翻译潜力的疗法。拟议的临床前研究将增加我们的 对微量出血(铁)引起的炎症的理解以及一种治疗方法的潜在益处 一种新的铁络合药物用于治疗严重影响质量的三种长期标志性脑损伤残疾 生活的一部分。该提案将测试一种新的六齿铁的安全性和有效性的临床前评估 螯合剂，NaHBED，用于清除微量出血诱导的铁，一种强有力的炎症催化剂，并上调 神经和血管营养剂，用于保护和修复受损的神经和血管组织。相应地，三个 提出了具体目标：具体目标1：将脑损伤引起的慢性疾病与细胞/分子联系起来 三个功能域测试行为的LC和特定神经底物的变化。马达测试， 焦虑、认知功能和全面的安全协议将在紧接之前和 每月治疗3个月，评价治疗的安全性和疗效。临床相关状态 ART磁化率加权成像(SWI)/定量磁化率成像(QSM)MRI和组织学 将进行免疫组织学实验以绘制除铁的时间进程和/或进一步 铁沉积。具体目标2：(治疗效果)。目的：确定NaHBED治疗慢性阻塞性肺疾病的疗效。 减轻长期的运动、认知和焦虑障碍。慢性治疗将在6个月后开始 使用初步工作中显示的剂量的TBI是有效的。此外，还介绍了时间特征和进展 NaHBED治疗后铁消除和/或进一步铁沉积(SWI/QSM MRI)，治疗 对慢性运动、焦虑和认知障碍的影响将在紧接之前和每月进行评估 治疗开始后3个月。具体目标3：确定NaHBED的安全性和有效性 在降低铁毒性和上调运动神经区细胞水平的营养因子方面， 认知和焦虑行为，使用全面的组织学、免疫组织化学和分子生物学方法 化验。我们认为，治疗将显著降低长期运动、认知和 焦虑障碍和这些改善将与a)细胞死亡、b)铁的显著减少相关 炎症和ROS的沉积和神经退行性标志物，c)血脑屏障标志物的正常化，以及d) 在提供关键信息的特定神经中枢中，神经和血管保护因子显著增加 研究行为的神经底物。这些慢性脑损伤研究针对特别强调的RR和D 对脑外伤导致的长期残疾和长期退行性疾病的关注(RX-18-014)。在……里面 具体地说，这些研究将提供关于脑外伤诱发因素的新见解，这些因素可能有助于 严重的慢性炎症导致的颅脑损伤残疾。由于这些风险因素在这两种影响中都很普遍 加速(车载)TBI以及冲击式TBI，它们影响VHS TBI的主要人群。如果我们的提议 慢性颅脑损伤的治疗被确定为安全有效，它适合立即治疗 转化为临床治疗和康复，因为它获得了IND对其他障碍的批准。

Traumatic brain injury (TBI) care and rehabilitation presents significant current and future challenges to the Veterans Health System (VHS). In addition to specific disabilities, there is a growing concern that TBI may significantly elevate risk factors for long-term chronic inflammation-induced progressive disease. Currently, effective therapies to address both of these issues are hampered by the lack of a sufficient neurobiological foundation to guide refinement of therapy for disability, and prevention strategies for chronic disease. Acceleration/deceleration TBI causes micro-vessel shear injury, blood brain barrier (BBB) dysfunction, and micro-bleeding. Iron deposited by diffuse micro-bleeds fuels inflammation through reactive oxygen species (ROS), and other inflammatory pathways may further induce progressive disabilities. There is an urgent need to address both specific disabilities and risk factors for long term progressive disease, and to develop effective therapies that have excellent potential for translation. The proposed pre-clinical studies will increase our understanding of microbleed (iron)-induced inflammation and the potential therapeutic benefits provided by a new iron chelating drug to address three long-term hallmark TBI disabilities that significantly impact the quality of life. The proposal will test the preclinical evaluation of the safety and efficacy of a new hexadentate iron chelator, NaHBED, to remove microbleed-induced iron, a powerful catalyst of inflammation, and to upregulate neural and vascular trophic agents to protect and heal injured neural and vascular tissues. Accordingly, three specific aims are proposed: Specific Aim 1: To correlate TBI-induced chronic disorders with cellular/molecular changes in LC and specific neural substrates of test behaviors in three functional domains. Tests for motor, anxiety, cognitive functions, and a comprehensive safety protocol will be conducted immediately before and monthly for 3 months post-treatment to evaluate the safety and efficacy of treatment. Clinically relevant state of the art Susceptibility weighted imaging (SWI)/Quantitative Susceptibility Mapping (QSM) MRI, and histological and immunohistological experiments will be performed to chart the time course for iron removal and/or further iron deposition. Specific Aim 2: (Therapeutic efficacy). To determine the efficacy of NaHBED therapy in mitigating long-term motor, cognitive and anxiety disabilities. Chronic treatment will be initiated at 6 months post- TBI using a dose shown in preliminary work to be effective. In addition, to temporal characteristics and progress of iron elimination and/or further iron deposition following NaHBED therapy (SWI/QSM MRI), the therapeutic impact on chronic motor, anxiety, and cognitive disabilities will be assessed immediately before and monthly for 3 months following the initiation of treatment. Specific Aim 3: To determine the safety and efficacy of NaHBED in reducing iron toxicity and up-regulating of trophic factors at the cellular level in the neural regions for motor, cognitive, and anxiety behaviors, using comprehensive histological, immunohistochemical, and molecular assays. We propose that treatment will significantly decrease the magnitude of long-term motor, cognitive and anxiety disabilities and these improvements will be correlated with significant decreases in a) cell death, b) iron deposition and neurodegenerative markers for inflammation and ROS, c) normalization of BBB markers, and d) significant increases in neural and vascular protective factors in the specific neural centers that provide key neural substrates for the studied behaviors. These chronic TBI studies address specifically highlighted RR&D concerns regarding TBI-induced long-term disabilities, and long-term degenerative disease (RX-18-014). In particular, these studies will provide new insights regarding TBI-induced factors that potentially contribute to significant chronic inflammation-induced TBI disabilities. Since these risk factors are prevalent in both impact acceleration (vehicular) TBI as well as blast TBI, they affect the predominant VHS TBI population. If our proposed treatment is determined to be safe and effective in the chronic TBI setting, it is well positioned for immediate translation to clinical treatment and rehabilitation since it obtained an IND approval for other disorder.