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

新型六齿铁螯合剂治疗啮齿动物模型中 TBI 引起的慢性残疾的功效和安全性

• 批准号: 10524736
• 负责人: PRODIP K. BOSE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524736
• 关键词: 3-nitrotyrosine; Acceleration; Address; Affect; Afghanistan; Aftercare; Amygdaloid structure; Animals; Anti-Inflammatory Agents; Anxiety; Anxiety Disorders; Apoptosis; Area; Behavior; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Caring; Cell Death; Cell Nucleus; Characteristics; Chelating Agents; Chronic; Chronic Disease; Clinical Treatment; Cognition Disorders; Cognitive; Data; Deceleration; Deferoxamine; Degenerative Disorder; Deposition; Diffuse; Diffuse Axonal Injury; Disease; Dose; Endothelium; Equilibrium; Excision; Florida; Foundations; Functional disorder; Future; Gait; Gait abnormality; Head; Health system; Healthcare; Healthcare Systems; Hemorrhage; Hippocampus (Brain); Histologic; Histology; Human; Immunohistochemistry; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-5; Intervention; Iraq; Iron; Legal patent; Magnetic Resonance Imaging; Measures; Mediating; Molecular; Morbidity - disease rate; Motor; NF-kappa B; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; New Agents; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Preclinical Testing; Predisposition; Prevention strategy; Progressive Disease; Protocols documentation; Quality of life; Reactive Oxygen Species; Rehabilitation therapy; Reporting; Research; Risk; Risk Factors; Rodent Model; Safety; Spastic Gait; Structure of thyroid parafollicular cell; TBI treatment; TNF gene; Testing; Therapeutic; Tight Junctions; Time; Tissues; Toxic effect; Translations; Traumatic Brain Injury; Treatment Efficacy; Universities; Up-Regulation; Vascular Endothelial Growth Factors; Vestibular nucleus structure; Veterans; Work; behavior test; behavioral study; biomarker evaluation; brain tissue; catalyst; chelation; clinically relevant; cognitive disability; cognitive function; disability; disability risk; effective intervention; effective therapy; equilibration disorder; experimental study; healing; in vivo; inflammatory marker; innovation; insight; locus ceruleus structure; motor disorder; nerve injury; nerve supply; neuroinflammation; noradrenergic; preclinical evaluation; preclinical study; protective factors; quantitative imaging; rehabilitation strategy; relating to nervous system; safety testing; sensory cortex; spasticity; therapy development; treatment strategy; vascular inflammation; white matter

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.

创伤性脑损伤（TBI）的护理和康复对患者提出了当前和未来的重大挑战。 退伍军人健康系统。除了特定的残疾，越来越多的人担心TBI可能 显著增加了长期慢性炎症诱导进行性疾病的危险因素。目前， 解决这两个问题的有效疗法由于缺乏足够的神经生物学机制而受到阻碍。 该基金会将指导完善残疾治疗和慢性病预防战略。 加速/减速TBI引起微血管剪切损伤、血脑屏障（BBB）功能障碍和脑损伤。 微出血弥漫性微出血沉积的铁通过活性氧簇刺激炎症 (ROS)和其他炎症途径可能进一步诱导进行性残疾。迫切需要 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 这些疗法具有很好的转化潜力。拟议的临床前研究将增加我们的 了解微出血（铁）诱导的炎症和潜在的治疗效益提供了一个 一种新的铁螯合药物，以解决三个长期的标志性TBI残疾，显着影响质量 生命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价 螯合剂，NaHBED，以去除微出血诱导的铁，一种强大的炎症催化剂，并上调 神经和血管营养剂以保护和治愈受损的神经和血管组织。因此，三 具体目标1：将TBI诱导的慢性疾病与细胞/分子 在三个功能域中的LC和测试行为的特定神经底物的变化。电机测试， 焦虑，认知功能和全面的安全协议将在术前立即进行， 治疗后3个月每月一次，以评估治疗的安全性和有效性。临床相关状态 磁敏感加权成像（SWI）/定量磁敏感成像（QSM）MRI和组织学 并进行免疫组织学实验以绘制铁去除的时间过程和/或进一步 铁沉积具体目标2：（疗效）。为了确定NaHBED治疗在 缓解长期的运动、认知和焦虑障碍。慢性治疗将在术后6个月开始， TBI使用初步工作中显示有效的剂量。此外，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）， 对慢性运动、焦虑和认知障碍的影响将在治疗前立即评估， 治疗开始后3个月。具体目标3：确定NaHBED的安全性和有效性 在运动神经区的细胞水平上降低铁毒性和上调营养因子， 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， 测定。我们认为，治疗将显着降低长期运动，认知和 焦虑障碍，这些改善将与a）细胞死亡，B）铁 c）BBB标志物的正常化，和d） 在特定的神经中枢，神经和血管保护因子的显着增加， 研究行为的神经基质。这些慢性TBI研究专门针对RR&D 关于TBI引起的长期残疾和长期退行性疾病的问题（RX-18-014）。在 特别是，这些研究将提供有关TBI诱导因素的新见解，这些因素可能有助于 显著慢性炎症诱发的TBI残疾。由于这些风险因素在两种影响中普遍存在， 加速（车辆）TBI以及冲击波TBI，它们影响主要的VHS TBI人群。如果我们的提议 治疗被确定为是安全和有效的慢性TBI设置，它是很好的定位，立即 由于它获得了用于其他疾病的IND批准，因此它被翻译为临床治疗和康复。