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: 10268189
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10268189
• 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) 护理和康复对当前和未来提出了重大挑战 退伍军人健康系统 (VHS)。除了特定的残疾之外，人们越来越担心 TBI 可能会导致 显着增加长期慢性炎症引起的进行性疾病的危险因素。现在， 由于缺乏足够的神经生物学研究，解决这两个问题的有效疗法受到阻碍 指导完善残疾治疗和慢性病预防策略的基础。 加速/减速 TBI 会导致微血管剪切损伤、血脑屏障 (BBB) 功能障碍以及 微出血。弥散性微出血沉积的铁通过活性氧促进炎症 （ROS）和其他炎症途径可能进一步诱发进行性残疾。迫切需要 解决特定的残疾和长期进展性疾病的风险因素，并制定有效的 具有巨大转化潜力的疗法。拟议的临床前研究将增加我们的 了解微出血（铁）引起的炎症以及微出血（铁）提供的潜在治疗益处 新型铁螯合药物可解决严重影响质量的三种长期标志性 TBI 残疾 的生活。该提案将测试新型六齿铁的安全性和有效性的临床前评估 螯合剂 NaHBED，可去除微出血引起的铁（炎症的强大催化剂）并上调 神经和血管营养剂，保护和治愈受伤的神经和血管组织。据此，三 提出了具体目标： 具体目标 1：将 TBI 诱发的慢性疾病与细胞/分子联系起来 LC 和三个功能域中测试行为的特定神经基质的变化。电机测试， 焦虑、认知功能和全面的安全方案将在之前和之后立即进行 治疗后 3 个月每月进行一次评估，以评估治疗的安全性和有效性。临床相关状态 最先进的磁敏感加权成像 (SWI)/定量磁敏感图 (QSM) MRI 和组织学 将进行免疫组织学实验来绘制铁去除和/或进一步的时间进程 铁沉积。具体目标2：（治疗效果）。确定 NaHBED 治疗的疗效 减轻长期运动、认知和焦虑障碍。慢性治疗将于6个月后开始 TBI 使用初步工作中显示的剂量是有效的。此外，时间特征和进展 NaHBED 治疗（SWI/QSM MRI）后的铁消除和/或进一步铁沉积，治疗 将在之前和每月评估对慢性运动、焦虑和认知障碍的影响 开始治疗后3个月。具体目标 3：确定 NaHBED 的安全性和有效性 减少铁毒性并上调运动神经区域细胞水平的营养因子， 认知和焦虑行为，利用综合组织学、免疫组织化学和分子 化验。我们建议治疗将显着降低长期运动、认知和 焦虑障碍和这些改善将与 a) 细胞死亡、b) 铁的显着减少相关 炎症和 ROS 的沉积和神经退行性标记物，c) BBB 标记物的正常化，以及 d) 特定神经中枢的神经和血管保护因子显着增加，提供关键 研究行为的神经基础。这些慢性 TBI 研究特别强调了 RR&D 对 TBI 引起的长期残疾和长期退行性疾病的担忧 (RX-18-014)。在 特别是，这些研究将为 TBI 诱发因素提供新的见解，这些因素可能会导致 严重的慢性炎症引起的 TBI 残疾。由于这些风险因素在两种影响中都很普遍 加速（车辆）TBI 以及爆炸 TBI，它们影响主要的 VHS TBI 人群。如果我们提出的 治疗被确定在慢性 TBI 环境中是安全有效的，它非常适合立即使用 自从获得其他疾病的 IND 批准后，它已转化为临床治疗和康复。